Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same

ABSTRACT

The invention relates to compounds of the formula 1  
                 
 
and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R 1  and R 2 , are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

BACKGROUND OF THE INVENTION

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 60/472,355, filed May 20, 2003, and U.S.Provisional Application No. 60/449,088, filed Feb. 21, 2003, both ofwhich are hereby incorporated by reference.

The invention relates to agents that inhibit hepatitis C virus (HCV)RNA-dependent RNA polymerase (RdRp). The invention also relates to theuse of such compounds in pharmaceutical compositions and therapeutictreatments useful for inhibition of HCV replication.

HCV is an enveloped RNA virus containing a single-strandedpositive-sense RNA genome approximately 9.5 kb in length (Choo et al.,Science 244:359-362 (1989)). The RNA genome contains a 5′-nontranslatedregion (5′ NTR) of 341 nucleotides (Brown et al., Nucl. Acids Res.20:5041-5045 (1992); Bukh et al., Proc. Natl. Acad. Sci. USA89:4942-4946 (1992)), a large open reading frame (ORF) encoding a singlepolypeptide of 3,010 to 3,040 amino acids (Choo et al. (1989), supra;),and a 3′-nontranslated region (3′-NTR) of variable length of about 230nucleotides (Kolykhalov et al., J. Virol. 70:3363-3371 (1996); Tanaka etal., J. Virol. 70:3307-3312 (1996)).

The 5′ NTR is one of the most conserved regions of the viral genome andplays a pivotal role in the initiation of translation of the viralpolyprotein (Bartenschlager (1997), supra). A single ORF encodes apolyprotein that is co- or post-translationally processed intostructural (core, E1, and E2) and nonstructural (NS2, NS3, NS4A, NS4B,NS5A, and NS5B) viral proteins by either cellular or viral proteinases(Bartenschlager (1997), supra). The 3′ NTR consists of three distinctregions: a variable region of about 38 nucleotides following the stopcodon of the polyprotein, a polyuridine tract of variable length withinterspersed substitutions of cystines, and 98 nucleotides (nt) at thevery 3′ end which are highly conserved among various HCV isolates. Theorder of the genes within the genome is:NH₂—C-E1-E2-p7-NS2—NS3-NS4A-NS4B-NS5A-NS5B-COOH (Grakoui et al., J.Virol. 67:1385-1395 (1993)).

Hepatitis C virus (HCV) is a member of the hepacivirus genus in thefamily Flaviviridae. It is the major causative agent of non-A, non-Bviral hepatitis and is the major cause of transfusion-associatedhepatitis and accounts for a significant proportion of hepatitis casesworldwide. Although acute HCV infection is often asymptomatic, nearly80% of cases resolve to chronic hepatitis. The persistent property ofthe HCV infection has been explained by its ability to escape from thehost immune surveillance through hypermutability of the exposed regionsin the envelope protein E2 (Weiner et al., Virology 180:842-848 (1991);Weiner et al. Proc. Natl. Acad. Sci. USA 89:3468-3472 (1992).

Processing of the structural proteins core (C), envelope protein 1 and(E1, E2), and the p7 region is mediated by host signal peptidases. Incontrast, maturation of the nonstructural (NS) region is accomplished bytwo viral enzymes. The HCV polyprotein is first cleaved by a host signalpeptidase generating the structural proteins C/E1, E1/E2, E2/p7, andp7/NS2 (Hijikata et al., Proc. Natl. Acad. Sci. USA 88:5547-5551 (1991);Lin et al., J. Virol. 68:5063-5073 (1994)). The NS2-3 proteinase, whichis a metalloprotease, then cleaves at the NS2/NS3 junction. The NS3/4Aproteinase complex (NS3 serine protease/NS4A cofactor), then at all theremaining cleavage sites (Bartenschlager et al., J. Virol. 67:3835-3844(1993); Bartenschlager (1997), supra). RNA helicase and NTPaseactivities have also been identified in the NS3 protein. The N-terminalone-third of the NS3 protein functions as a protease, and the remainingtwo-thirds of the molecule acts as a helicase/ATPase, which is thoughtto be involved in HCV replication (Bartenschlager (1997), supra). NS5Amay be phosphorylated and act as a putative cofactor of NS5B. The fourthviral enzyme, NS5B, is an RNA-dependent RNA polymerase (RdRp) and a keycomponent responsible for replication of the viral RNA genome (Lohmannet al., J. Virol. 71:8416-8428 (1997)).

Replication of HCV is thought to occur in membrane-associatedreplication complexes. Within these, the genomic plus-strand RNA istranscribed into minus-strand RNA, which in turn can be used as atemplate for synthesis of progeny genomic plus strands. Two viralproteins appear to be involved in this reaction: the NS3 protein, whichcarries in the carboxy terminal two-thirds a nucleosidetriphosphatase/RNA helicase, and the NS5B protein, which is amembrane-associated phosphoprotein with an RNA-dependent RNA polymeraseactivity (RdRp) (Hwang et al., J. Virol. 227:439-446 (1997)). While therole of NS3 in RNA replication is less clear, NS5B apparently is the keyenzyme responsible for synthesis of progeny RNA strands. Usingrecombinant baculoviruses to express NS5B in insect cells and asynthetic nonviral RNA as a substrate, two enzymatic activities havebeen identified as being associated with NS5B. The two activitiesinclude a primer-dependent RdRp and a terminal transferase (TNTase)activity. NS5B's activity was confirmed and further characterizedthrough the use of the HCV RNA genome as a substrate (Lohmann et al.,Virology 249:108-118 (1998)). Recent studies have shown that NS5B with aC-terminal 21 amino-acid truncation expressed in Escherichia coli isalso active for in vitro RNA synthesis (Ferrari et al., J. Virol.73:1649-1654 (1999); Yamashita et al., J. Biol. Chem. 273:15479-15486(1998)).

Since persistent infection of HCV is related to chronic hepatitis andeventually to hepatocarcinogenesis, HCV replication is one of thetargets to eliminate HCV reproduction and to prevent hepatocellularcarcinoma. Unfortunately, present treatment approaches for HCV infectionare characterized by relatively poor efficacy and an unfavorableside-effect profile. Therefore, intensive effort is directed at thediscovery of molecules to treat this disease, including the discovery ofdrugs designed to inhibit HC replication, as there is a persistent needfor non-peptide, small-molecule compounds that are HCV RdRp inhibitorshaving desirable or improved physical and chemical propertiesappropriate for pharmaceutical applications.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

and to pharmaceutically acceptable salts, hydrates, metabolites,prodrugs and solvates thereof, wherein:

-   -   W-Z is —C(═O)—C(—R³)(H)— or —C(—OR⁶)═C(—R^(3′))—, wherein when        W-Z is —C(—OR⁶)═C(R^(3′))—;    -   each R¹ is independently selected from hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₃-C₁₀) cycloalkyl, 4- to        10-membered heterocyclic, and C₆-C₁₀ aryl, wherein the foregoing        R¹ groups, except H, are optionally substituted by 1 to 4        substituents selected from R⁴;    -   R² is selected from the group of R¹ substituents,        —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), —(CR⁸R⁹)_(t)(4-10 membered        heterocyclic), —(CR⁸R⁹)_(q)C(O)(CR⁸R⁹)_(t)(C₆-C₁₀ aryl),        —(CR⁸R⁹)_(q)C(O)(CR⁸R⁹)_(t)(4-10 membered heterocyclic),        —(CR⁸R⁹)_(t)O(CR⁸R⁹)_(q)(C₆-C₁₀ aryl),        —(CR⁸R⁹)_(t)O(CR⁸R⁹)_(q)(4-10 membered heterocyclic),        —(CR⁸R⁹)_(q)SO_(n)(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(q)SO_(n)(CR⁸R⁹)_(t)(4-10 membered heterocyclic),        wherein q and t are each independently an integer from 0 to 5, n        is an integer from 0 to 2, the alkyl, aryl and heterocyclic        moieties of said R² groups are optionally substituted by 1 to 5        R⁴ groups, and with the proviso that R² is not H;    -   R³ is hydrogen, —OR⁶, —SR⁶, —NR⁶R⁷, and the group of R²        substituents;    -   R^(3′) is selected from the group of R³ substituents except        R^(3′) is not H;    -   each R⁴ is independently selected from halo, cyano, nitro,        trifluoromethoxy, trifluoromethyl, azido, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —NR⁶SO₂R⁷,        —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl)(wherein t is an integer from 0 to 5),        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic)(wherein t is an integer        from 0 to 5), C₃-C₁₀ cycloalkyl, R⁶—O—, R⁶—SO_(n)— (wherein n is        an integer from 0 to 2), and oxo (═O), and wherein the alkyl,        aryl, and heterocyclic moieties of said R⁴ groups are optionally        substituted by 1 to 4 substituents selected from R⁵;    -   each R⁵ is independently selected from halo, trifluoromethyl,        trifluoromethoxy, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —OR⁸, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 4- to 10-membered        heterocyclic, oxo (═O), —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁶,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —NR⁶SO₂R⁷ and        —SO₂NR⁶R⁷, wherein the alkyl, aryl and heterocyclic moieties of        the foregoing R⁵ groups are optionally substituted by 1 to 3        R¹⁰;    -   each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,        C₃-C₁₀ cycloalkyl, —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t is an        integer from 0 to 5, 1 or 2 ring carbon atoms of the        heterocyclic group are optionally substituted with an oxo (═O)        moiety, and the alkyl, aryl and heterocyclic moieties of the        foregoing R⁶ and R⁷ groups are optionally substituted with 1 to        3 halo, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(CR⁸R⁹)_(t)(C₆-C₁₀        aryl), and —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t        is an integer from 0 to 5;    -   each R⁸ and R⁹ is independently selected from H and C₁-C₄ alkyl;        and    -   each R¹⁰ is independently selected from halo, cyano,        trifluoromethyl, trifluoromethoxy, —C(O)O—R⁶, —OR⁶,        —C(O)(CR⁸R⁹)_(p)C(O)OR⁶, wherein p is an integer from 1 to 5,        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and —NR⁶R⁷.

The present invention also relates to compounds of formula (1), wherein:

-   -   W-Z is —C(═O)—C(—R³)(H)— or —C(—OR⁶)═C(—R^(3′))—;    -   each R¹ is independently selected from hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₃-C₁₀) cycloalkyl, 4- to        10-membered heterocyclic, and C₆-C₁₀ aryl, wherein the foregoing        R¹ groups, except H, are optionally substituted by 1 to 4        substituents selected from R⁴;    -   R² is selected from the group of R¹ substituents,        —(CR⁸R⁹)_(t)(C₃-C₁₀ cycloalkyl), —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl),        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic),        —(CR⁸R⁹)_(q)C(O)(CR⁸R⁹)_(t)(C₆-C₁₀ aryl),        —(CR⁸R⁹)_(q)C(O)(CR⁸R⁹)_(t)(4-10 membered heterocyclic),        —(CR⁸R⁹)_(t)O(CR⁸R⁹)_(q)(C₆-C₁₀ aryl),        —(CR⁸R⁹)_(t)O(CR⁸R⁹)_(q)(4-10 membered heterocyclic),        —(CR⁸R⁹)_(q)SO_(n)(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(q)SO_(n)(CR⁸R⁹)_(t)(4-10 membered heterocyclic),        wherein q and t are each independently an integer from 0 to 5, n        is an integer from 0 to 2, the alkyl, cycloalkyl, aryl and        heterocyclic moieties of said R² groups are optionally        substituted by 1 to 5 R⁴ groups, and with the proviso that R² is        not H;    -   R³ is hydrogen, —OR⁶, —SR⁶, —NR⁶R⁷, and the group of R²        substituents;    -   R^(3′) is selected from the group of R³ substituents;    -   each R⁴ is independently selected from halo, cyano, nitro,        trifluoromethoxy, trifluoromethyl, azido, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, —(CR⁸R⁹)_(t)N(R⁵)₂,        —(CR⁸R⁹)_(t)NR⁶C(O)R⁶, —(CR⁸R⁹)_(t)OR⁶, —(CR⁸R⁹)_(t)C(O)R⁶,        —(CR⁸R⁹)_(t) C(O)OR⁶, —(CR⁸R⁹)_(t)C(O)R⁶, —(CR⁸R⁹)_(t)        NR⁶C(O)R⁷, —(CR⁸R⁹)_(t)NR⁶C(O)OR⁶—(CR⁸R⁹)_(t)NR⁶C(O)NR⁷,        —(CR⁸R⁹)_(t)C(O)NR R⁷, —(CR⁸R⁹)_(t)NR⁶R⁷, —(CR⁸R⁹)_(t)NR⁶OR⁷,        —(CR⁸R⁹)_(t)SO₂NR⁶R⁷, —(CR⁸R⁹)_(t)NR⁶SO₂R⁷, —(CR⁸R⁹)_(t)(C₆-C₁₀        aryl)(wherein t is an integer from 0 to 5), —(CR⁸R⁹)_(t)(4-10        membered heterocyclic)(wherein t is an integer from 0 to 5),        C₃-C₁₀ cycloalkyl, R⁶—O—, R⁶—SO_(n)—(CR⁸R⁹)_(t)— (wherein n is        an integer from 0 to 2), and oxo (═O), and wherein the alkyl,        aryl, and heterocyclic moieties of said R⁴ groups are optionally        substituted by 1 to 4 substituents selected from R⁵;    -   each R⁵ is independently selected from halo, trifluoromethyl,        trifluoromethoxy, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —OR⁸, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 4- to 10-membered        heterocyclic, oxo (═O), —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁶,        —NR⁶C(O)NR⁷—C(O)NR⁶R⁷—NR⁶R⁷, —NR⁶OR⁷, —NR⁶SO₂R⁷ and —SO₂NR⁶R⁷,        wherein the alkyl, aryl and heterocyclic moieties of the        foregoing R⁵ groups are optionally substituted by 1 to 3 R¹⁰;    -   each R⁶ and R⁷ is independently selected from H, cyano, C₁-C₆        alkyl, C₃-C₁₀ cycloalkyl, —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), —(CR⁸R⁹)_(t)C(O)R⁸        wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of        the heterocyclic group are optionally substituted with an oxo        (═O) moiety, and the alkyl, aryl and heterocyclic moieties of        the foregoing R⁶ and R⁷ groups are optionally substituted with 1        to 3 halo, cyano, C₃-C₁₀ cycloalkyl, —C(O)OR⁸—NR⁸C(O)R⁹,        —(CR⁸R⁹)_(t)NR⁸R⁹, —OR⁸, —NC(O)R⁹, trifluoromethyl,        trifluoromethoxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and —(CR⁸R⁹)_(t)(4-10        membered heterocyclic), wherein t is an integer from 0 to 5;    -   each R⁸ and R⁹ is independently selected from H and C₁-C₄ alkyl;        and    -   each R¹⁰ is independently selected from halo, cyano,        trifluoromethyl, trifluoromethoxy, —C(O)OR⁶, —C(O)O—R⁶, —OR⁶,        —C(O)(CR⁸R⁹)_(p)C(O)OR⁶, wherein p is an integer from 1 to 5,        C—C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and —NR⁶R⁷.

The present futher relates to a comound of the formula 2

and pharmaceutically acceptable salts, solvates, metabolites, prodrugsand solvates thereof, wherein:

-   -   W-Z is —C(—OR⁶)═C(—R^(3′));    -   R¹ is cyclopentyl;    -   R² is —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl) or —(CR⁸R⁹)_(t)(4-10 membered        heterocyclic), wherein t is an integer from 0 to 5, and the aryl        and heterocyclic moieties of said R² groups are optionally        substituted by 1 to 5 R⁴ groups, and with the proviso that R² is        not H;    -   R³ is hydrogen, —OR⁶, —SR⁶, —NR⁶R⁷, and the group of R²        substituents;    -   each R⁴ is independently selected from halo, cyano, nitro,        trifluoromethoxy, trifluoromethyl, azido, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷,        —NR⁶SO₂R⁷—(CR⁸R⁹)_(t)(C₆-C₁₀ aryl)(wherein t is an integer from        0 to 5), —(CR⁸R⁹)_(t)(4-10 membered heterocyclic)(wherein t is        an integer from 0 to 5), C₃-C₁₀ cycloalkyl, R⁶—O—,        R⁶—SO_(n)—(wherein n is an integer from 0 to 2), and oxo (═O),        and wherein the alkyl, aryl, and heterocyclic moieties of said        R⁴ groups are optionally substituted by 1 to 4 substituents        selected from R⁵;    -   each R⁵ is independently selected from halo, trifluoromethyl,        trifluoromethoxy, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —OR⁸, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 4- to 10-membered        heterocyclic, oxo (═O), —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁶,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —NR⁶SO₂R⁷ and        —SO₂NR⁶R⁷, wherein the alkyl, aryl and heterocyclic moieties of        the foregoing R⁵ groups are optionally substituted by 1 to 3        R¹⁰;    -   each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,        C₃-C₁₀ cycloalkyl, —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t is an        integer from 0 to 5, 1 or 2 ring carbon atoms of the        heterocyclic group are optionally substituted with an oxo (═O)        moiety, and the alkyl, aryl and heterocyclic moieties of the        foregoing R⁶ and R⁷ groups are optionally substituted with 1 to        3 halo, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CR⁸R⁹)_(t)(C₆-C₁₀        aryl), and —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t        is an integer from 0 to 5;    -   each R⁸ and R⁹ is independently selected from H and C₁-C₄ alkyl;        and    -   each R¹⁰ is independently selected from halo, cyano,        trifluoromethyl, trifluoromethoxy, —C(O)O—R⁶, —OR⁶,        —C(O)(CR⁸R⁹)pC(O)OR wherein p is an integer from 1 to 5, C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and NR⁶R⁷.

The present invention further relates to a compound of the formula (3)

and to pharmaceutically acceptable salts, solvates, prodrugs, andmetabolites thereof, wherein:

-   -   W-Z is —C(═O)—C(—R³)(H)—;    -   R¹ is cyclopentyl;    -   R² is —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl) or —(CR⁸R⁹)_(t)(4-10 membered        heterocyclic), wherein t is an integer from 0 to 5, and the aryl        and heterocyclic moieties of said R² groups are optionally        substituted by 1 to 5 R⁴ groups, and with the proviso that R² is        not H;    -   R³ is hydrogen;    -   each R⁴ is independently selected from halo, cyano, nitro,        trifluoromethoxy, trifluoromethyl, azido, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —NR⁶SO₂R⁷,        —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl)(wherein t is an integer from 0 to 5),        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic)(wherein t is an integer        from 0 to 5), C₃-C₁₀ cycloalkyl, R⁶—O—, R⁶—SO_(n)— (wherein n is        an integer from 0 to 2), and oxo (═O), and wherein the alkyl,        aryl, and heterocyclic moieties of said R⁴ groups are optionally        substituted by 1 to 4 substituents selected from R⁵;    -   each R⁵ is independently selected from halo, trifluoromethyl,        trifluoromethoxy, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —OR⁸, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, 4- to 10-membered        heterocyclic, oxo (═O), —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁶,        —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —NR⁶SO₂R⁷ and        —SO₂NR⁶R⁷, wherein the alkyl, aryl and heterocyclic moieties of        the foregoing R⁵ groups are optionally substituted by 1 to 3        R¹⁰;    -   each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,        C₃-C₁₀ cycloalkyl, —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), and        —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t is an        integer from 0 to 5, 1 or 2 ring carbon atoms of the        heterocyclic group are optionally substituted with an oxo (═O)        moiety, and the alkyl, aryl and heterocyclic moieties of the        foregoing R⁶ and R⁷ groups are optionally substituted with 1 to        3 halo, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CR⁸R⁹)_(t)(C₆-C₁₀        aryl), and —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t        is an integer from 0 to 5;    -   each R⁸ and R⁹ is independently selected from H and C₁-C₄ alkyl;        and    -   each R¹⁰ is independently selected from halo, cyano,        trifluoromethyl, trifluoromethoxy, —C(O)O—R⁶, —OR⁶,        —C(O)(CR⁸R⁹)pC(O)OR⁶, wherein p is an integer from 1 to 5, C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and NR⁶R⁷.

In a specific embodiment of the present invention, according to formula1, R² is —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), wherein t is an integer from 2 to 5,and the aryl moiety of said R² group is optionally substituted by 1 to 5R⁴ groups, and with the proviso that R² is not H; optionally each R⁴ isindependently selected from halo, nitro, C₁-C₁₀ alkyl, —C(O)R⁶,—C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁷, —(CR⁸R⁹)_(t)(4-10 memberedheterocyclic)(wherein t is an integer from 0 to 5), C₃-C₁₀ cycloalkyl,R⁶—O—, and wherein the alkyl, aryl, and heterocyclic moieties of said R⁴groups are optionally substituted by 1 to 4 substituents selected fromR⁵, optionally each R⁵ is independently selected from halo,trifluoromethyl, C₁-C₆ alkyl, —OR⁸, C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, oxo(═O), —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁶, —NR⁶C(O)NR⁷, —C(O)NR⁶R⁷,—NR⁶R⁷, —NR⁶OR⁷, —NR⁶SO₂R⁷ and —SO₂NR⁶R⁷, wherein the alkyl and arylmoieties of the foregoing R⁵ groups are optionally substituted by 1 to 3R¹⁰; optionally each R¹⁰ is independently selected from halo,trifluoromethyl, —C(O)O—R⁶, —OR⁶, C₁-C₆ alkyl and NR⁶R⁷; optionally R³is —OR⁶, —SR⁶, —NR⁶R⁷, and —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl), wherein t is aninteger from 2 to 5, and the aryl moiety of said R² group is optionallysubstituted by 1 to 5 R⁴ groups.

In yet another aspect of the present invention are provided compounds offormula (4),

wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CR⁸R⁹)_(t)(C₆-C₁₀ aryl) or —(CR⁸R⁹)_(t)(4-10 membered        heterocyclic), wherein t is an integer from 0 to 5, and the aryl        and heterocyclic moieties of said R³ groups are optionally        substituted by 1 to 5 R⁴ groups;    -   each R⁴ is independently chosen from halo, C₁-C₁₀ alkyl, and        R⁶—O—, and each C₁-C₁₀ alkyl may be optionally substituted by at        least one substituent chosen from halo, trifluoromethyl,        trifluoromethoxy, C₁-C₁₀ alkyl, and cyano; or when two adjacent        R⁴ groups are both C₁-C₁₀ alkyl, they, together with the atoms        to which they are attached, form a 3- to 7-membered ring,        wherein in said ring any carbon atom may be replaced by a        heteroatom chosen from N, O, and S, provided that two adjacent        carbons are not both replaced by heteroatoms;    -   R⁶ is hydrogen or C₁-C₁₀ alkyl;    -   R⁸ and R⁹ are independently chosen from hydrogen and C₁-C₁₀        alkyl;    -   z is an integer from 1 to 5; and    -   y is an integer from 0 to 5.

In a further aspect of the present invention are provided compounds offormula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CR⁸R⁹)_(t)(4-10 membered heterocyclic), wherein t is an        integer from 0 to 5, and the heterocyclic moiety is optionally        substituted by 1 to 5 R⁴ groups;    -   each R⁴ is independently chosen from halo, C₁-C₁₀ alkyl, and        R⁶—O—, and each C₁-C₁₀ alkyl may be optionally substituted by at        least one substituent chosen from halo, trifluoromethyl,        trifluoromethoxy, C₁-C₁₀ alkyl, and cyano; or when two adjacent        R⁴ groups are both C₁-C₁₀ alkyl, they, together with the atoms        to which they are attached, form a 3- to 7-membered ring,        wherein in said ring any carbon atom may be replaced by a        heteroatom chosen from N, O, and S, provided that two adjacent        carbons are not both replaced by heteroatoms;    -   R⁶ is hydrogen or C₁-C₁₀ alkyl;    -   R⁸ and R⁹ are hydrogen;    -   z is an integer from 1 to 5; and    -   y is an integer from 0 to 5.

In yet another aspect of the present invention are provided compounds offormula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)_(t)([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally        substituted by 1 to 3 R⁴ groups;    -   t is an integer from 1-3;    -   each R⁴ is independently chosen from halo, C₁-C₁₀ alkyl, and        R⁶—O—, and each C₁-C₁₀ alkyl may be optionally substituted by at        least one substituent chosen from halo, trifluoromethyl,        trifluoromethoxy, C₁-C₁₀ alkyl, and cyano; or    -   when two adjacent R⁴ groups are both C₁-C₁₀ alkyl, they,        together with the atoms to which they are attached, form a 3- to        7-membered ring, wherein in said ring any carbon atom may be        replaced by a heteroatom chosen from N, O, and S, provided that        two adjacent carbons are not both replaced by heteroatoms;    -   R⁶ is hydrogen or C₁-C₁₀ alkyl;    -   z is an integer from 1 to 5; and    -   y is an integer from 1 to 3.

In still a further aspect of the present invention are providedcompounds of formula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by        1 to 3 R⁴ groups;    -   each R⁴ is independently chosen from halo and C₁-C₁₀ alkyl        optionally substituted with cyano; or    -   two adjacent R⁴ groups are both C₁-C₁₀ alkyl and, together with        the atoms to which they are attached, form a 3- to 7-membered        ring, wherein a carbon atom is replaced by a heteroatom chosen        from N, O, and S;    -   z is an integer from 2 to 3; and    -   y is 2.

In yet another aspect of the present invention are provided compounds offormula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by        2 R⁴ groups;    -   each R⁴ is independently chosen from halo, —CH₃, and —C(CH₃)₂CN;        and    -   y is 2.

In still a further aspect of the present invention are providedcompounds of formula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by        at least one substituent chosen from halo and methyl;    -   two adjacent R⁴ groups, together with the atoms to which they        are attached form a 5-membered ring, wherein in said ring one        carbon atom is replaced by O;    -   z is an integer from 2 to 3; and    -   y is 2.

In yet another aspect of the present invention are provided compounds offormula (4b),

wherein:

-   -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by        at least one substituent chosen from halo and methyl;    -   Q is chosen from N, O, and S;    -   R^(4a), R^(4b), and R^(4c) are independently chosen from        hydrogen, halo, C₁-C₁₀ alkyl, and R⁶—O—; and    -   R⁶ is chosen from hydrogen and C₁-C₁₀ alkyl.

Another aspect of the present invention provides compounds of formula(5),

wherein:

-   -   R^(4a), R^(4b), and R^(4c) are independently chosen from halo        and C₁-C₁₀ alkyl;    -   R^(4d), R^(4e), and R^(4f) are independently chosen from halo,        R⁶—O—, and C₁-C₁₀ alkyl, wherein said C₁-C₁₀ alkyl is optionally        substituted with at least one substituent chosen from halo and        cyano; and    -   R⁶ is C₁-C₁₀ alkyl or hydrogen.

Another aspect of the present invention provides compounds of formula(6),

wherein R⁴ is halo.

In still a further aspect of the present invention provides compounds offormula (7),

wherein R⁴ is halo.

Another aspect of the present invention provides compounds of formula(8),

-   -   wherein R⁴ is halo.

Still a further aspect of the present invention provides compounds offormulas (6), (7), and (8), wherein R⁴ is chosen from fluorine andchlorine. In yet another aspect of the present invention are providedcompounds of formulas (6), (7), and (8), wherein R⁴ is fluorine. Instill a further aspect are provided those compounds of formula (6), (7),and (8), wherein R⁴ is chlorine.

Another aspect of the present invention provides compounds of formula(4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally        substituted by 1 to 3 R⁴ groups;    -   each R⁴ is independently chosen from halo, C₁-C₁₀ alkyl, and        R⁶—O—, and each C₁-C₁₀ alkyl may be optionally substituted by at        least one substituent chosen from halo, trifluoromethyl,        trifluoromethoxy, C₁-C₁₀ alkyl, and cyano;    -   R⁶ is hydrogen or C₁-C₁₀ alkyl;    -   z is an integer from 1 to 3; and    -   y is 2.

In still a further aspect of the present invention are providedcompounds of formula (4), wherein:

-   -   R¹ is cyclopentyl;    -   R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally        substituted by 1 to 3 R⁴ groups;    -   each R⁴ is independently chosen from halo, C₁-C₁₀ alkyl, and        R⁶—O—, and each C₁-C₁₀ alkyl may be optionally substituted by at        least one substituent chosen from halo, trifluoromethyl,        trifluoromethoxy, C₁-C₁₀ alkyl, and cyano;    -   R⁶ is hydrogen or methyl;    -   z is an integer from 2-3; and    -   y is 2.

In still a further aspect of the present invention are providedcompounds of formula (9),

wherein:

R^(4a) is halo or C₁-C₁₀ alkyl;

-   -   R^(4b), R^(4c), and R^(4d) are independently chosen from C₁-C₁₀        alkyl and R⁶—O—; and    -   R⁶ is hydrogen or methyl.

Also provided in the present invention are compounds of formula (9),wherein:

-   -   R^(4a) is halo;    -   R^(4b) and R^(4c) are each R⁶—O—;    -   R^(4d) is C₁-C₁₀ alkyl; and    -   R⁶ is hydrogen or methyl.

In another aspect of the present invention are provided compounds offormula (9), wherein:

-   -   R^(4a) is fluorine or chlorine;    -   R^(4b) is —OCH₃;    -   R^(4c) is —OH; and    -   R^(4d) is —CH₂CH₃.

Another aspect provides compounds of formula (9), wherein:

-   -   R^(4a) is chlorine;    -   R^(4b) is —OCH₃;    -   R^(4c) is —OH; and    -   R^(4d) is —CH₂CH₃.

Another aspect of the present invention provides compounds of formula(10),

Still a further aspect of the present invention provides compounds offormula (11),

In another embodiment of the present invention, the invention relates toa compound selected from the group consisting of:

-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a-pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-cyclopentyl-3-[(5,7-dimethyl    [1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione;-   7-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;-   2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;-   6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one;-   6    N-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]4,6-dioxotetrahydro-2H-pyran-2-yl}ethyl)-2-ethylphenyl]-N-methylmethanesulfonamide;-   2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(1-methyl-1H-indol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;-   6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   3-(5-Chloro-1-isopropyl-1-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   5-{6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}4-methyl-4H-[1,2,4]triazole-3-carboxylic    acid methyl ester;-   3-(5-Chloro-1-methyl-1H-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-{[5-(2-furyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one;-   6-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   8-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-1,7-dihydro-6H-purin-6-one;-   6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[5-(4-hydroxyphenyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one;-   ethyl    2-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)(1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate;-   6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;-   2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile;-   2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   (+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   (−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile;-   1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;-   1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,    6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;-   6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[2,4]triazolo[1,    5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one;-   3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-hydroxy-3-propylphenyl)ethyl]-5,6-dihydro-2H-pyran-2-one;-   6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;-   2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;-   2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile;-   2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile    (+)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one    (−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,    5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;    and    pharmaceutically acceptable salts, solvates and prodrugs of the    foregoing compounds.

The present invention also provides compounds chosen from:

-   2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;-   2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   (+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   (−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;-   N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;-   2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;-   (+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one    (−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one    1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,    5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;    and    the pharmaceutically acceptable salts, solvates and prodrugs of the    foregoing compounds.

In a further aspect, the invention relates to compounds chosen from:

-   6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;-   7-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;-   2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;-   1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,    5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;-   6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one;-   2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(1-methyl-1H-indol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-cyclopentyl-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   (+)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   (−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;    6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;-   (+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;    and pharmaceutically acceptable salts, solvates and prodrugs of the    foregoing compounds.

In yet another aspect of the present invention are provided compoundschosen from:

-   (+)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-fluoro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;-   (+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   (−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   (−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;-   6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;    and    pharmaceutically acceptable salts, solvates and prodrugs of the    foregoing compounds.

The invention also relates to a method for the treatment of Hepatitis Cvirus (HCV) in a mammal, such as a human, comprising administering tosaid mammal an amount of a compound of the present invention or a saltor solvate thereof that is effective in treating HCV.

In a further aspect of the present invention are provided methods forthe treatment of a mammal, such as a human, suffering from infectionwith Hepatitis C virus, comprising administering to said mammal aHepatitis C virus-inhibiting amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug,pharmaceutically active metabolite, or solvate thereof. The presentinvention also relates to a method of inhibiting Hepatitis C polymerase,comprising contacting said polymerase with a polymerase-inhibitingamount of a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, pharmaceutically active metabolite, or solvatethereof.

The present invention is also directed to a pharmaceutical compositionfor the treatment of Hepatitis C virus (HCV) in a mammal, such as ahuman, comprising an amount of a compound the present invention, or apharmaceutically acceptable salt, prodrug, pharmaceutically activemetabolite, or solvate thereof, that is effective in treating HCV, and apharmaceutically acceptable carrier.

The present invention is also directed to inhibition of Hepatitis Cvirus replication in a mammal, such as a human, comprising administeringto said mammal a Hepatitis C virus replication-inhibiting amount of acompound of the present invention.

The present invention is further directed to a method of inhibiting HCVRdRp activity, comprising contacting the protein with an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, pharmaceutically active metabolite, or solvatethereof. For Example, HCV activity may be inhibited in mammalian tissueby administering an HCV-inhibiting agent according to the invention.

The present invention also relates to the use of the compounds of theinvention in the preparation of a medicament for the treatment of amammal suffering from infection with Hepatitis C virus. The medicamentmay comprise a Hepatitis C virus-inhibiting amount of a compound orcompounds of the invention and a pharmaceutically acceptable carrier orcarriers.

As used herein, the terms “comprising” and “including” are used in theiropen, non-limiting sense.

In accordance with a convention used in the art, the symbol

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure. In accordance with another convention, in some structuralformulae herein the carbon atoms and their bound hydrogen atoms are notexplicitly depicted, e.g.,

represents a methyl group,

represents an ethyl group,

represents a cyclopentyl group, etc.

The compounds of the present invention may exist in several tautomericforms. For example, a compound of the invention may exist in a form inwhich two ketones are present on a ring of the compound, as shown in (A)below. Alternatively, the compounds of the present invention may existin at least two different enol forms, as shown in compounds (B) and (C)below. These three forms may be in equilibrium and the compounds of theinvention may exist in more than one of these forms at the same time.For example, in a particular compound of the invention, a certainpercentage of the molecules may be present in form (A) while theremainder are present in form (B) or form (C). Which form predominatesin a particular compound of the invention depends on several factorsthat include, but are not limited to, whether the compound is in solid,liquid, or crystalline form, whether the compound is dissolved in asolvent and the identity of the solvent, the environmental temperature,and the relative humidity. It is specifically contemplated that when thecompounds of the present invention are drawn in a particular form, form(A) for example, all the tautomeric forms, forms (B) and (C) forexample, are included as well.

The term “C₁-C₆ alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched, or cyclic moieties (including fused and bridged bicyclic andspirocyclic moieties), or a combination of the foregoing moieties, andcontaining from 1-6 carbon atoms. For an alkyl group to have cyclicmoieties, the group must have at least three carbon atoms.

A “lower alkyl” is intended to mean an alkyl group having from 1 to 4carbon atoms in its chain. The term “heteroalkyl” refers to a straight-or branched-chain alkyl group having from 2 to 12 atoms in the chain,one or more of which is a heteroatom selected from S, O, and N.Exemplary heteroalkyls include alkyl ethers, secondary and tertiaryamines, alkyl sulfides and the like.

The term “C₂-C₆ alkenyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon double bondwherein alkyl is as defined above and including E and Z isomers of saidalkenyl moiety, and having from 2 to 6 carbon atoms.

The term “C₂-C₆ alkynyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon triple bondwherein alkyl is as defined above, and containing from 2-6 carbon atoms.

The term “carbocycle” refers to a saturated, partially saturated,unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic,ring structure having only carbon ring atoms (no heteroatoms, i.e.,non-carbon ring atoms). Exemplary carbocycles include cycloalkyl, aryl,and cycloalkyl-aryl groups.

A “C₃-C₁₀ cycloalkyl group” is intended to mean a saturated or partiallysaturated, monocyclic, or fused or spiro polycyclic, ring structurehaving a total of from 3 to 10 carbon ring atoms (but no heteroatoms).Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and like groups.

A “heterocycloalkyl group” is intended to mean a monocyclic, or fused orspiro polycyclic, ring structure that is saturated or partiallysaturated, and has a total of from 3 to 18 ring atoms, including 1 to 5heteroatoms selected from nitrogen, oxygen, and sulfur. IllustrativeExamples of heterocycloalkyl groups include pyrrolidinyl,tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,aziridinyl, and like groups.

The term “C₆-C₁₀ aryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen, such as phenyl or naphthyl.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system,and with the proviso that the ring of said group does not contain twoadjacent O or S atoms. Furthermore, the sulfur atoms contained in suchheterocyclic groups may be oxidized with one or two sulfur atoms.Non-aromatic heterocyclic groups include groups having only 4 atoms intheir ring system, but aromatic heterocyclic groups must have at least 5atoms in their ring system. The heterocyclic groups include benzo-fusedring systems. An example of a 4 membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An exampleof a heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl.

A “heteroaryl group” is intended to mean a monocyclic or fused or spiropolycyclic, aromatic ring structure having from 4 to 18 ring atoms,including from 1 to 5 heteroatoms selected from nitrogen, oxygen, andsulfur. Illustrative Examples of heteroaryl groups include pyrrolyl,thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl, pyrazinyl,triazolyl, tetrazolyl, indolyl, quinolinyl, quinoxalinyl, benzthiazolyl,benzodioxinyl, benzodioxolyl, benzooxazolyl, and the like.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein alkyl is as defined above.

The term “amino” is intended to mean the —NH₂ radical.

The terms “halogen” and “halo,” as used herein represent chlorine,fluorine, bromine or iodine.

The term “trifluoromethyl,” as used herein, is meant to represent agroup —CF₃.

The term “trifluoromethoxy,” as used herein, is meant to represent agroup —OCF₃.

The term “cyano,” as used herein, is meant to represent a group —CN.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents.

The term “HCV,” as used herein, refers to Hepatitis C virus.

The term “inhibiting Hepatitis C virus” means inhibiting Hepatitis Cvirus replication in a mammal, such as a human, by administering to themammal a Hepatitis C virus-inhibiting amount of a compound of theinvention. The amount of inhibition of Hepatitis C virus replication ina mammal can be measured using methods known to those of ordinary skillin the art. For example, an amount of a compound of the invention may beadministered to a mammal, either alone or as part of a pharmaceuticallyacceptable formulation. Blood samples may then be withdrawn from themammal and the amount of Hepatitis C virus in the sample may bequantified using methods known to those of ordinary skill in the art. Areduction in the amount of Hepatitis C virus in the sample compared tothe amount found in the blood before administration of a compound of theinvention would represent inhibition of the replication of Hepatitis Cvirus in the mammal. The administration of a compound of the inventionto the mammal may be in the form of single dose or a series of dosesover successive days.

An “HCV-inhibiting agent” means a compound of the present invention or apharmaceutically acceptable salt, hydrate, prodrug, active metabolite orsolvate thereof.

The term “HCV-inhibiting amount,” as used herein, refers to an amount ofa compound of the present invention that is sufficient to inhibit thereplication of the Hepatitis C virus when administered to a mammal, suchas a human.

The term “HCV polymerase-inhibiting amount,” as used herein, means anamount of a compound of the present invention that is sufficient toinhibit the function of the Hepatitis C virus polymerase enzyme when thecompound is placed in contact with the enzyme.

A “prodrug” is a compound that may be converted under physiologicalconditions or by solvolysis to the specified compound or to apharmaceutically acceptable salt of such compound. A prodrug may be aderivative of one of the compounds of the present invention thatcontains a moiety, such as for example —CO₂R, —PO(OR)₂ or —C═NR, thatmay be cleaved under physiological conditions or by solvolysis. Anysuitable R substituent may be used that provides a pharmaceuticallyacceptable solvolysis or cleavage product. A prodrug containing such amoiety may be prepared according to conventional procedures by treatmentof a hydroxamate derivative of this invention containing, for example,an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent.An “active metabolite” is a pharmacologically active product producedthrough metabolism in the body of a specified hydroxamate derivative orsalt thereof. Prodrugs and active metabolites of the hydroxamatederivative may be identified using routine techniques known in the art.See, e.g., Bertolini et al., J. Med. Chem., 40:2011-2016 (1997); Shan etal., J. Pharm. Sci., 86 (7):765-767 (1997); Bagshawe, Drug Dev. Res.,34:220-230 (1995); Bodor, Advances in Drug Res., 13:224-331 (1984);Bundgaard, “Design of Prodrugs” (Elsevier Press, 1985); Larsen, Designand Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al. eds., Harwood Academic Publishers, 1991); Dearet al., Chromatogr. B, 748:281-293 (2000); Spraul et al., J.Pharmaceutical & Biomedical Analysis, 10 (8):601-605 (1992); and Prox etal., Xenobiol, 3(2):103-112 (1992).

A “solvate” is intended to mean a pharmaceutically acceptable solvateform of a specified compound that retains the biological effectivenessof such compound. Examples of solvates include compounds of theinvention in combination with solvents such as, but not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,or ethanolamine. A “pharmaceutically acceptable salt” is intended tomean a salt that retains the biological effectiveness of the free acidsand bases of the specified derivative and that is not biologically orotherwise undesirable. Examples of pharmaceutically acceptable saltsinclude sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups, which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of the present invention arethose that form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edislyate, estolate, esylate,ethylsuccinate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate,nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phospate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodode, and valerate salts.

The phrases “therapeutically effective amount,” “effective amount,” and“HCV-inhibiting amount,” are intended to mean the amount of an inventiveagent that, when administered to a mammal in need of treatment, issufficient to effect treatment for injury or disease conditionsalleviated by the inhibition of HCV RNA replication such as forpotentiation of anti-cancer therapies or inhibition of neurotoxicityconsequent to stroke, head trauma, and neurodegenerative diseases. Theamount of a given HCV-inhibiting agent used in the method of theinvention that will be therapeutically effective will vary dependingupon factors such as the particular HCV-inhibiting agent, the diseasecondition and the severity thereof, the identity and characteristics ofthe mammal in need thereof, which amount may be routinely determined byartisans.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may have asymmetric carbon atoms.The carbon-carbon bonds of the compounds of the present invention may bedepicted herein using a solid line

a solid wedge

or a dotted wedge

The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers at that carbon atomare included. The use of either a solid or dotted wedge to depict bondsto asymmetric carbon atoms is meant to indicate that only thestereoisomer shown is meant to be included. It is possible thatcompounds of the invention may contain more than one asymmetric carbonatom. In those compounds, the use of a solid line to depict bonds toasymmetric carbon atoms is meant to indicate that all possiblestereoisomers are meant to be included. The use of a solid line todepict bonds to one or more asymmetric carbon atoms in a compound of theinvention and the use of a solid or dotted wedge to depict bonds toother asymmetric carbon atoms in the same compound is meant to indicatethat a mixture of diastereomers is present.

Solutions of individual stereoisomeric compounds of the presentinvention may rotate plane-polarized light. The use of either a “(+)” or“(−)” symbol in the name of a compound of the invention indicates that asolution of a particular stereoisomer rotates plane-polarized light inthe (+) or (−) direction, as measured using techniques known to those ofordinary skill in the art.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention.

Alternatively, individual stereoisomeric compounds of the presentinvention may be prepared in enantiomerically enriched form byasymmetric synthesis. Asymmetric synthesis may be performed usingtechniques known to those of skill in the art, such as the use ofasymmetric starting materials that are commercially available or readilyprepared using methods known to those of ordinary skill in the art, theuse of asymmetric auxiliaries that may be removed at the completion ofthe synthesis, or the resolution of intermediate compounds usingenzymatic methods. The choice of such a method will depend on factorsthat include, but are not limited to, the availability of startingmaterials, the relative efficiency of a method, and whether such methodsare useful for the compounds of the invention containing particularfunctional groups. Such choices are within the knowledge of one ofordinary skill in the art.

When the compounds of the present invention contain asymmetric carbonatoms, the derivative salts, prodrugs and solvates may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates, and mixturesthereof are intended to be within the scope of the present invention.

As generally understood by those skilled in the art, an optically purecompound is one that is enantiomerically pure. As used herein, the term“optically pure” is intended to mean a compound comprising at least asufficient activity. Preferably, an optically pure amount of a singleenantiomer to yield a compound having the desired pharmacological purecompound of the invention comprises at least 90% of a single isomer (80%enantiomeric excess), more preferably at least 95% (90% e.e.), even morepreferably at least 97.5% (95% e.e.), and most preferably at least 99%(98% e.e.).

If a derivative used in the method of the invention is a base, a desiredsalt may be prepared by any suitable method known to the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; andthe like, or with an organic acid, such as acetic acid; maleic acid;succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid;oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such asglucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citricacid or tartaric acid; amino acid, such as aspartic acid or glutamicacid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid; and thelike.

If a derivative used in the method of the invention is an acid, adesired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary, or tertiary); an alkali metal oralkaline earth metal hydroxide; or the like. Illustrative Examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine; ammonia; primary, secondary, and tertiary amines;and cyclic amines, such as piperidine, morpholine, and piperazine; aswell as inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

In the case of derivatives, prodrugs, salts, or solvates that aresolids, it is understood by those skilled in the art that thederivatives, prodrugs, salts, and solvates used in the method of theinvention, may exist in different polymorph or crystal forms, all ofwhich are intended to be within the scope of the present invention andspecified formulas. In addition, the derivative, salts, prodrugs andsolvates used in the method of the invention may exist as tautomers, allof which are intended to be within the broad scope of the presentinvention.

The compounds of the present invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as methanol orethanol. Upon careful evaporation of the solvent, the desired solid saltis readily obtained. The desired acid salt can also be precipitated froma solution of the free base in an organic solvent by adding to thesolution an appropriate mineral or organic acid.

Those compounds of the present invention that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

The activity of the compounds as inhibitors of HCV activity may bemeasured by any of the suitable methods available in the art, includingin vivo and in vitro assays. An Example of a suitable assay for activitymeasurements is the HCV replicon assay described herein.

Administration of the compounds and their pharmaceutically acceptableprodrugs, salts, active metabolites, and solvates may be performedaccording to any of the accepted modes of administration available tothose skilled in the art. Illustrative Examples of suitable modes ofadministration include oral, nasal, parenteral, topical, transdermal,and rectal. Oral and intravenous deliveries are preferred.

An HCV-inhibiting agent of the present invention may be administered asa pharmaceutical composition in any suitable pharmaceutical form.Suitable pharmaceutical forms include solid, semisolid, liquid, orlyopholized formulations, such as tablets, powders, capsules,suppositories, suspensions, liposomes, and aerosols. The HCV-inhibitingagent may be prepared as a solution using any of a variety ofmethodologies. For Example, the HCV-inhibiting agent can be dissolvedwith acid (e.g., 1 M HCl) and diluted with a sufficient volume of asolution of 5% dextrose in water (D5W) to yield the desired finalconcentration of HCV-inhibiting agent (e.g., about 15 mM).Alternatively, a solution of D5W containing about 15 mM HCl can be usedto provide a solution of the HCV-inhibiting agent at the appropriateconcentration. Further, the HCV-inhibiting agent can be prepared as asuspension using, for example, a 1% solution of carboxymethylcellulose(CMC).

Acceptable methods of preparing suitable pharmaceutical forms of thepharmaceutical compositions are known or may be routinely determined bythose skilled in the art. For Example, pharmaceutical preparations maybe prepared following conventional techniques of the pharmaceuticalchemist involving steps such as mixing, granulating, and compressingwhen necessary for tablet forms, or mixing, filling, and dissolving theingredients as appropriate, to give the desired products for oral,parenteral, topical, intravaginal, intranasal, intrabronchial,intraocular, intraaural, and/or rectal administration.

Pharmaceutical compositions of the invention may also include suitableexcipients, diluents, vehicles, and carriers, as well as otherpharmaceutically active agents, depending upon the intended use. Solidor liquid pharmaceutically acceptable carriers, diluents, vehicles, orexcipients may be employed in the pharmaceutical compositions.Illustrative solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesiumstearate, and stearic acid. Illustrative liquid carriers include syrup,peanut oil, olive oil, saline solution, and water. The carrier ordiluent may include a suitable prolonged-release material, such asglyceryl monostearate or glyceryl distearate, alone or with a wax. Whena liquid carrier is used, the preparation may be in the form of a syrup,elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g.,solution), or a nonaqueous or aqueous liquid suspension.

A dose of the pharmaceutical composition may contain at least atherapeutically effective amount of an HCV-inhibiting agent andpreferably is made up of one or more pharmaceutical dosage units. Theselected dose may be administered to a mammal, for example, a human, inneed of treatment mediated by inhibition of HCV activity, by any knownor suitable method of administering the dose, including topically, forexample, as an ointment or cream; orally; rectally, for example, as asuppository; parenterally by injection; intravenously; or continuouslyby intravaginal, intranasal, intrabronchial, intraaural, or intraocularinfusion. When the composition is administered in conjunction with acytotoxic drug, the composition can be administered before, with, and/orafter introduction of the cytotoxic drug. However, when the compositionis administered in conjunction with radiotherapy, the composition ispreferably introduced before radiotherapy is commenced.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15^(th) Edition (1975).

It will be appreciated that the actual dosages of the HCV-inhibitingagents used in the pharmaceutical compositions of this invention will beselected according to the properties of the particular agent being used,the particular composition formulated, the mode of administration andthe particular site, and the host and condition being treated. Optimaldosages for a given set of conditions can be ascertained by thoseskilled in the art using conventional dosage-determination tests. Fororal administration, e.g., a dose that may be employed is from about0.001 to about 1000 mg/kg body weight, preferably from about 0.1 toabout 100 mg/kg body weight, and even more preferably from about 1 toabout 50 mg/kg body weight, with courses of treatment repeated atappropriate intervals.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in the compounds of the presentinvention, but for the fact that one or more atoms are replaced by anatom having an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples and Preparations below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

EXAMPLES

Specific Examples of various compounds according to the invention may beadvantageously prepared as set out in the Examples above. These examplesand the compounds contained therein are not meant to limit the scope ofthe present invention in any way.

The structures of the compounds of the following Examples were confirmedby one or more of the following: proton magnetic resonance spectroscopy,infrared spectroscopy, elemental microanalysis, mass spectrometry, thinlayer chromatography, melting point, boiling point, and HPLC.

Proton magnetic resonance (¹H NMR) spectra were determined using a 300megahertz Tech-Mag, Bruker Avance 300DPX, or Bruker Avance 500 DRXspectrometer operating at a field strength of 300 or 500 megahertz(MHz). Chemical shifts are reported in parts per million (ppm, δ)downfield from an internal tetramethylsilane standard. Alternatively, ¹HNMR spectra were referenced to residual protic solvent signals asfollows: CHCl₃=7.26 ppm; DMSO=2.49 ppm; C₆HD₅=7.15 ppm. Peakmultiplicities are designated as follows: s=singlet; d=doublet;dd=doublet of doublets; t=triplet; q=quartet; br=broad resonance; andm=multiplet. Coupling constants are given in Hertz. Infrared absorption(IR) spectra were obtained using a Perkin-Elmer 1600 series FTIRspectrometer. Elemental microanalyses were performed by AtlanticMicrolab Inc. (Norcross, Ga.) and gave results for the elements statedwithin ±0.4% of the theoretical values. Flash column chromatography wasperformed using Silica gel 60 (Merck Art 9385). Analytical thin layerchromatography (TLC) was performed using precoated sheets of Silica 60F₂₅₄ (Merck Art 5719). HPLC chromatographs were run on a Hewlett PackardModel 1100 system fitted with a Zorbax SB-C18 4.6 mm×150 mm columnhaving 3.5 micron packing material. Unless otherwise stated, a ramp of5% CH₃CN/H₂O to 95% CH₃CN/H₂O over 7.5 minutes then holding at 95%CH₃CN/H₂O for 2.5 minutes (both solvents contained 0.1% v/v TFA) at aflow of 1 mL/min was used. Retention times (Rt) are given in minutes.Semi-preparative HPLC samples were run on a Gilson LC3D system fittedwith a 21.2 mm×250 mm C8 column. Ramps were optimized for each compoundwith a CH₃CN/H₂O solvent system. Melting points were determined on aMel-Temp apparatus and are uncorrected. All reactions were performed inseptum-sealed flasks under a slight positive pressure of argon, unlessotherwise noted. All commercial reagents were used as received fromtheir respective suppliers with the following exceptions:tetrahydrofuran (THF) was distilled from sodium-benzophenone ketyl priorto use; dichloromethane (CH₂Cl₂) was distilled from calcium hydrideprior to use; anhydrous lithium chloride was prepared by heating at 110°C. under vacuum overnight. Mass spectra, both low and high resolution,were measured using either electrospray (EI) or fast atom bombardment(FAB) ionization techniques.

The following abbreviations are used herein: Et₂O (diethyl ether); DMF(N,N-dimethylformamide); DMSO (dimethylsulfoxide); MeOH (methanol); EtOH(ethanol); EtOAc (ethyl acetate); Ac (acetyl); Hex (hexane); Me(methyl); Et (ethyl); Ph (phenyl); DIEA (diisopropylethylamine); TFA(trifluoroacetic acid); DTT (dithiothreitol); and THF (tetrahydrofuran);and (precipitate); min. or min (minutes); h (hours).

Solid-phase syntheses were performed by immobilizing reagents with Rinkamide linkers (Rink, Tetrahedron Letters (1987) 28:3787), which arestandard acid-cleavable linkers that upon cleavage generate a freecarboxamide group. Small-scale solid-phase syntheses, e.g., about 2-5μmole, were performed using Chiron SynPhase® polystyrene O-series crowns(pins) derivatized with Fmoc-protected Rink amide linkers. For largerscale (e.g., greater than about 100 μmole) syntheses, the Rink amidelinkages were formed to Argonaut Technologies Argogel® resin, a graftedpolystyrene-poly(ethylene glycol) copolymer. Any suitable resin may beused as the solid phase, selected from resins that are physicallyresilient and that, other than with regard to the linking and cleavagereactions, are inert to the synthetic reaction conditions.

Example A(1)6-Cyclopentyl-6-[2-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where5-Bromo-1-ethyl-1H-pyridin-2-one was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.35 (t, J=7.2 Hz, 3H), 1.52-1.81 (brm, 8H), 1.87 (m,2H), 2.28 (m, 1H), 2.45 (t, J=8.5 Hz, 2H), 2.72 (d, J=16 Hz, 1H), 2.80(d, J=16 Hz, 1H), 3.43 (s, 2H), 3.96 (q, J=7.2 Hz, 2H), 6.54 (d, J=9.2Hz, 1H), 7.06 (s, 1H), 7.14 (d, J=9.2 Hz, 1H). Anal. Calcd. ForC₁₉H₂₅N₁O₄: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.74; H, 7.42; N,4.34.

Example A(2)6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(22), where4-Bromo-2-tert-butyl-phenol from Step 1, was used in place of4-Bromo-2-ethyl-phenol in Step 2 of that example.

¹H NMR (CDCl₃): δ 1.39 (s, 9H,), 1.43-1.85 (br m, 8H), 1.87-2.01 (m,2H), 2.27 (m, 1H), 2.60 (t, J=8.4 Hz, 2H), 2.77 (s, 2H), 3.42 (s, 2H),4.74 (s, 1H), 6.60 (d, J=8.1 Hz 1H)), 6.84 (d, J=8.1 Hz, 1H), 7.00 (s,1H).

Step 1. 4-Bromo-2-tert-butyl-phenol

2-tert-Butyl-phenol (5 g, 0.033 mol) was dissolved in CHCl₃ (100 mL) andmagnetically stirred at room temperature. To this solution was added asolution of Tetrabutyl ammonium tribromide (16.05 g, 0.033 mol) in CHCl₃(100 mL). The resulting yellow solution was allowed to stir at roomtemperature for 1 hour. The reaction was quenched with a 5% solution ofsodium thiosulfate (200 mL). The biphasic mixture was stirred for 15min. The organics were separated and concentrated. The residue wasdissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine(1×100 mL). The organics were dried over Na2SO4, filtered andconcentrated. The residue was purified by flash chromatography (silicagel) eluting with 3% EtOAc in Hexanes. The result was a clear oil (6.8g, 89%).

¹H NMR (CDCl₃): δ 1.39 (s, 9H), 4.95 (s, 1H), 6.59 (d, J=8.5 Hz 1H),7.19 (d, J=8.5 Hz, 1H), 7.24 (s, 1H).

Example A(3) 6-Cyclopentyl-6-[2-(4-ethxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where4-Bromo-1-ethoxy-2-methyl-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.40 (t, J=7 Hz, 3H), 1.52-1.81 (brm, 8H), 1.99 (m,2H), 2.19 (s, 3H), 2.30 (m, 1H), 2.58 (t, J=8.6 Hz, 2H), 2.76 (s, 2H),3.41 (s, 2H), 4.00 (q, J=7 Hz, 2H), 6.71 (d, J=8.8 Hz, 1H), 6.89 (m,2H). Anal. Calcd. For C₂₁H₂₈O₄: C, 73.23; H, 8.19. Found: C, 73.12; H,8.22.

Example A(4)6-Cyclopentyl-6-[2-(4-isopropoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where4-Bromo-1-isopropoxy-2-methyl-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.30 (d, J=6.2 Hz, 6H), 1.52-1.81 (brm, 8H), 1.99 (m,2H), 2.15 (s, 3H), 2.37 (m, 1H), 2.58 (t, J=8.6 Hz, 2H), 2.74 (s, 2H),3.42 (s, 2H), 4.43 (m, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.88 (m, 2H). Anal.Calcd. For C₂₂H₃₀O₄: C, 73.71; H, 8.44. Found: C, 73.64; H, 8.22.

Example A(5)6-{2-[3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where was4-Bromo-2-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene substituted in placeof 2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.44-1.77 (brm, 8H), 1.92 (m, 2H), 2.27 (m, 1H), 2.63(m, 2H), 2.74 (d, J=15.8 Hz, 1H), 2.79 (d, J=15.8 Hz, 1H), 3.43 (s, 2H),4.35 (d, J=8.1 Hz, 1H), 4.40 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H),7.02 (d, J=8.5 Hz, 1H), 7.19 (s, 1H). Anal. Calcd. For C₂₀H₂₂ClF₃O₄: C,57.35; H, 5.29. Found: C, 57.55; H, 5.12.

Example A(6)6-Cyclopentyl-6-(4-methoxy-phenylsulfanylmethyl)-dihydro-pyran-2,4-dione

1-Cyclopentyl-2-(4-methoxy-phenylsulfanyl)-ethanone (from Step 2 below)was subjected to the methyl acetoacetate dianion addition reactiondescribed in the synthesis of Example A(82), to yield the title compoundas a white solid.

¹H NMR (CDCl₃): δ 1.35-1.86 (brm, 8H), 2.35 (m, 1H), 2.61-3.62 (m, 6H),3.85 (s, 3H), 6.82 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).

Step 1: 2-Chloro-1-cyclopentyl-ethanone

Cyclopentanecarbonyl chloride (5.0 g, 0.038 mol) was dissolved in THF(100 mL) and cooled to 0° C. The solution was treated with a 2M solutionof TMS-Diazomethane in hexanes (56.56 mL, 0.113 mol) over 10 min. Theresulting yellow solution was allowed to stand at room temperature for12 hours. The solution was then concentrated and the residue wasdissolved in THF (100 mL) and treated slowly with a 4N HCl in Dioxanesolution (28.28 mL, 0.113 mol). The result was allowed to stir at 24° C.for 2 hours. The solution was concentrated to an oil which waschromatographed on silica gel eluting with 5% EtOAc in Hexanes to givethe intermediate depicted below (4.9 g, 88%).

¹H NMR (CDCl₃): δ 1.62-1.98 (m, 8H), 3.12-3.25 (m, 1H), 4.21 (s, 2H).

Step 2: 1-Cyclopentyl-2-(4-methoxy-phenylsulfanyl)-ethanone

The intermediate 2-Chloro-1-cyclopentyl-ethanone from Step 1 (1 g, 6.81mmol), was combined with 4-methoxy-benzenethiol (1.05 g, 7.50 mmol), inTHF (20 mL) and treated with Triethylamine (1.05 mL, 7.50 mmol). Themixture was stirred for 1 hour at room temperature then poured intowater (50 mL) and extracted with EtOAc (2×50 mL). The organics were thenwashed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) andbrine (lx 50 mL) the organics were dried over Na₂SO₄, filtered andconcentrated. The residue was used without further purification (1.65 g,97%).

Example A(7)N-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-acetamide

The title compound was prepared analogously to Example A(64), whereN-(4-Bromo-2-fluoro-phenyl)-acetamide was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.55-1.77 (br m, 8H), 1.94 (m, 2H), 2.21 (s, 3H), 2.26(m, 1H), 2.65 (m, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 6.90 (m, 2H), 8.19(t, 1H, J=8.3 Hz). ESIMS: (M+H)⁺384.05.

Example A(8)6-Cyclopentyl-6-[2-(3-fluoro-4-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-Bromo-2-fluoro-1-methoxymethyl-benzene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.55-1.80 (br m, 8H), 1.95 (m, 2H), 2.27 (m, 1H), 2.68(m, 2H), 2.76 (s, 2H), 3.40 (s, 3H), 3.43 (s, 2H), 4.48 (s, 2H), 6.85(d, 1H, J=9.6 Hz), 6.93 (d, 1H, J=6.2 Hz), 7.32 (t, 1H, J=7.7 Hz). Anal.Calcd. For C₂₀H₂₅O₄F: C, 68.77; H, 7.11; Found: C, 68.90; H, 7.23.

Example A(9)6-Cyclopentyl-6-[2-(2-fluoro-biphenyl-4-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-Bromo-2-fluoro-biphenyl was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹HNMR(CDCl₃): δ 1.55-1.83 (br m, 8H), 2.0 (m, 2H), 2.30 (m, 1H), 2.72(m, 2H), 2.79 (s, 2H), 3.45 (s, 2H), 6.96 (d, 1H, J=11.7 Hz), 7.0 (d,1H, J=7.9 Hz), 7.36 (m, 2H), 7.44 (m, 2H), 7.52 (m, 2H). Anal. Calcd.For C₂₄H₂₅O₃F: C, 75.76; H, 6.62; Found: C, 75.56; H, 6.66.

Example A(10)6-[2-(4-Benzo[b]thiophen-2-yl-3-fluoro-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-2-fluoro-phenyl)-benzo[b]thiophene (described below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of thatexample.

¹H NMR (CDCl₃): δ 1.55-1.83 (br m, 8H), 2.0 (m, 2H), 2.29 (m, 1H), 2.73(m, 2H), 2.79 (s, 2H), 3.45 (s, 2H), 6.98 (d, 1H, J=6.0 Hz), 7.0 (s,1H), 7.34 (m, 2H), 7.62 (t, 1H, J=10.5 Hz), 7.70 (s, 1H), 7.82 (m, 2H).ESIMS: MH⁻435.05.

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-benzo[b]thiophene

A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol),1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol),bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO₃(0.83 g, 9.9 mmol) in DME (4 mL) and H₂O (4 mL) was heated to 80° C.under N₂ for 72 h. The reaction mixture was partitioned between 1N HCland EtOAc. The organic layer was washed with saturated NaHCO₃, brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (hexanes) to give the title compound as a white solid(0.13 g, 13%).

¹H NMR (CDCl₃): δ 7.33-7.41 (m, 4H), 7.57 (m, 1H), 7.72 (s, 1H),1.80-7.86 (m, 2H).

Example A(11)4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-N-methyl-benzamide

The title compound was prepared analogously to Example A(64), where4-Bromo-2-fluoro-N-methyl-benzamide (described below), was substitutedin place of 4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.46-1.80 (br m, 8H), 1.96 (m, 2H), 2.27 (m, 1H), 2.73(m, 2H), 2.77 (d, 2H, J=5.3 Hz), 3.03 (d, 3H, J=4.5 Hz), 3.44 (s, 2H),6.71 (br s, 1H), 6.91 (d, 1H, J=12.8 Hz), 7.05 (d, 1H, J=9.2 Hz), 8.10(t, 1H, J=8.0 Hz). Anal. Calcd. For C₂₀H₂₄NO₄F.0.3H₂O: C, 65.48; H,6.76; N, 3.82. Found: C, 65.29; H, 6.48; N, 3.56.

Step 1: 4-Bromo-2-fluoro-N-methyl-benzamide

A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol),methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine(1.0 mL, 7.3 mmol) dissolved in CH₂Cl₂(15 mL) was stirred under N₂ for24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. Theorganic layers were washed with saturated NaHCO₃, brine, dried overdried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (40% EtOAc in hexanes) to give the title compound asa white solid (0.27 g, 32%).

¹H NMR (CDCl₃): δ 3.03 (d, 3H, J=6.0 Hz), 6.68 (br s, 1H), 7.32 (d, 1H,J=11.3 Hz), 7.42 (d, 1H, J=10.2 Hz), 8.01 (t, 1H, J=8.5 Hz).

Example A(12)6-cyclopentyl-6-{2-[3-fluoro-4-(5-methyl-thiophen-2-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-2-fluoro-phenyl)-5-methyl-thiophene (described below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of thatexample.

¹H NMR (CDCl₃): δ 1.55-1.80 (br m, 8H), 1.97 (m, 2H), 2.28 (m, 1H), 2.51(s, 3H), 2.68 (m, 2H), 2.78 (s, 2H), 3.44 (s, 2H), 6.75 (d, 1H, J=4.5Hz), 6.90 (d, 1H, J=2.6 Hz), 6.93 (s, 1H), 7.22 (d, 1H, J=2.5 Hz), 7.48(t, 1H, J=8.3 Hz). Anal. Calcd. For C₂₃H₂₅O₃SF: C, 68.97; H, 6.29.Found: C, 69.29; H, 6.24.

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-5-methyl-thiophene

A mixture of 5-methyl-2-thiophene-boronic acid (1 g, 7.0 mmol),1-bromo-3-fluoro-4-iodobenzene (1.77 g, 5.9 mmol),tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.3 mmol), 2MNa₂CO₃(10 mL) in DME (10 mL) was heated to 75° C. under N₂ for 15 h. Thereaction mixture was partitioned between 1 N HCl and EtOAc. The organiclayer was washed with saturated NaHCO₃, brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(hexanes) to give the title compound (1.2 g, 75%).

¹H NMR (CDCl₃): δ 2.52 (s, 3H), 6.76 (s, 1H), 7.25-7.32 (m, 3H), 7.43(t, 1H, J=8.5 Hz).

Example A(13)6-(2-Cyclohex-1-enyl-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione

Methyl acetoacetate (0.66 g, 5.7 mmol) was added to a cooled 0° C.suspension of NaH (0.23 g, 5.7 mmol, 60% dispersion in mineral oil) inTHF (10 ml). After 30 min n-BuLi (2.3 mL, 5.7 mmol, 2.5M in hexanes) wasadded. The resulting dianion was stirred for an additional 30 min andthen treated with a solution3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one (0.39 g, 1.9 mmol, Step 4below) in THF (3 ml). After stirring for 4 h at 0° C., the reactionmixture was quenched with 1N HCl and extracted with EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to anorange oil that was used without further purification. The oil wasdissolved in methanol (8 mL), treated with potassium carbonate (0.79 g,5.7 mmol), and refluxed under N₂ for 90 min. The reaction mixture waspartitioned between 1N HCl and EtOAc. The organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to an orange oil that waspurified by silica gel chromatography (0% to 20% EtOAc in hexanes). togive the title compound as a white solid. (0.22 g, 40% yield).

¹H NMR (CDCl₃): δ 1.42-1.98 (br m, 20H), 2.22 (m, 1H), 2.71 (s, 2H),3.40 (s, 2H), 5.40 (s, 1H). Anal. Calcd. For C₁₈H₂₆O₃.0.2H₂O: C, 75.53;H, 9.05. Found: C, 73.74; H, 9.01.

Step 1: 3-Cyclohex-1-Enyl-Propionic Acid Ethyl Ester

The title compound was prepared as described in the following reference:JOC, 1998, 63, 2755-57.

Step 2: 3-Cyclohex-1-Enyl-Propionic Acid

2N LiOH (3.5 mL) was added to a solution of 3-Cyclohex-1-enyl-propionicacid ethyl ester (0.6 g, 3.4 mmol, from Step 1) dissolved in THF (12 mL)and MeOH (3 mL). The mixture was stirred for 2 h under N₂ and thenpartitioned between 1N HCl and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated to a clear oil.

¹H NMR (CDCl₃): δ 1.54 (m, 2H), 1.62 (m, 2H), 1.92 (m, 2H), 1.97 (m,2H), 2.26 (m, 2H), 2.46 (t, 2H, J=8.3 Hz), 5.44 (s, 1H).

Step 3: 3-Cyclohex-1-enyl-thiopropionic Acid S-pyridin-2-yl Ester

A solution of 3-Cyclohex-1-enyl-propionic acid (0.47 g, 3.04 mmol, fromStep 2), triphenylphosphine (1.04 g, 3.95 mmol) and 2,2′-dipyridyldisulfide (0.87 g, 3.95 mmol) dissolved in CH₂Cl₂ (12 mL) was stirredunder N₂ for 3 h. The reaction mixture was concentrated to a yellow oiland purified by silica gel chromatography (5% to 20% EtOAc in hexanes)to give the title compound as a yellow oil (0.7 g, 93%).

¹H NMR (CDCl₃): δ 1.55 (m, 2H), 1.63 (m, 2H), 1.94 (m, 2H), 1.99 (m,2H), 2.35 (t, 2H, J=7.3 Hz), 2.81 (t, 2H, J=8.0 Hz), 5.47 (s, 1H), 7.28(dd, 1H, J=7.8, 4.8 Hz), 7.61 (d, 1H, J=7.8 Hz), 7.74 (td, 1H, J=7.8Hz), 8.61 (d, 1H, J=4.8 Hz).

Step 4: 3-cyclohex-1-enyl-1-cyclopentyl-propan-1-one. {TB-4059-095}

Cyclopentylmagnesium bromide (1.6 mL, 3.15 mmol, 2M soln in ether) wasadded to a cooled −78° C. solution of 3-Cyclohex-1-enyl-thiopropionicacid S-pyridin-2-yl ester (0.65 g, 2.63 mmol, from Step 3) dissolved inTHF (10 mL). The reaction mixture was stirred for 45 min at −78° C. andthen warmed up to rt. The reaction was quenched with 1 N HCl andextracted with EtOAc. The organic layer was washed with saturatedNaHCO₃, brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (0% to 5% EtOAc in hexanes) togive the title compound as a clear oil (0.39 g, 72%).

¹H NMR (CDCl₃): δ 1.51-1.83 (br m, 12H), 1.91 (m, 2H), 1.97 (m, 2H),2.20 (t, 2H, J=7.6 Hz), 2.54 (t, 2H, J=7.8 Hz), 2.87 (m, 1H), 5.39 (s,1H).

Example A(14)6-Cyclopentyl-6-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared as described in Example A(13), where1-(3-Cyclopentyl-3-oxo-propyl)-pyrrolidin-2-one (described in Step 2below) was substituted in place of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹H NMR (CDCl₃): δ 1.41-1.84 (br m, 9H), 1.98-2.21 (m, 4H), 2.37 (m, 2H),2.67 (d, 1H, J=15.8 Hz), 3.08 (d, 1H, J=15.8 Hz), 3.28-3.51 (m, 5H),3.61 (m, 1H). Anal. Calcd. For C₁₆H₂₃NO₄: C, 63.55; H, 8.00; N, 4.63.Found: C, 63.41; H, 8.04; N, 4.52.

Step 1: 3-(2-Oxo-pyrrolidin-1-yl)-propionic Acid

A solution of 2-oxo-1-pyrrolidinepropionitrile (22.4 g, 16.2 mmol), 15%NaOH solution (40 mL) and dioxane (40 mL) was heated under reflux for 5h under N₂. The reaction mixture was extracted with EtOAc. The aqueouslayer was made acidic with 6N HCl amd extracted with CH₂Cl₂ (5×50 mL).The organic layers were dried over Na₂SO₄ and concentrated to give thetitle compound as a cream solid (12.4 g, 49%).

¹H NMR (CDCl₃): δ 2.04 (m, 2H), 2.42 (t, 2H, J=7.9 Hz), 2.60 (t, 2H,J=6.8 Hz), 3.48 (t, 2H, J=7.2 Hz), 3.59 (t, 2H, J=6.8 Hz), 10.29 (br s,1H).

Step 2: 1-(3-Cyclopentyl-3-oxo-propyl)-pyrrolidin-2-one

2-Chloro-4-6-dimethoxy-1,3,5-triazine (2.68 g, 15.2 mmol) andN-methylmorpholine (4.2 mL, 38.1 mmol) were added to a solution of3-(2-Oxo-pyrrolidin-1-yl)-propionic acid (2 g, 12.7 mmol, from Step 1)in THF (35 mL). After 1 h the reaction mixture was filtered through aglass frit to remove a white precipitate. The filtrate was treated withcopper iodide (2.4 g, 12.7 mmol), cooled to 0° C. and then cyclopentylmagnesium bromide (6.35 mL, 12.7 mmol, 2M in ether) was added. After 4 hthe resulting black mixture was quenched with saturated NH₄Cl andextracted with CH₂Cl₂. The organic layers were washed with 1 N HCl,saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated. The residuewas purifed by silica gel chromatography (75% EtOAc in hexanes then 5%MeOH in CH₂Cl₂) to give the title compound as a yellow oil. (0.4 g, 15%yield).

¹H NMR (CDCl₃): δ 1.55-1.83 (br m, 8H), 1.99 (m, 3H), 2.35 (t, 2H, J=8.3Hz), 2.74 (t, 2H, J=6.8 Hz), 3.41 (d, 2H, J=7.2 Hz), 3.53 (t, 2H, J=6.6Hz).

Example A(15)6-Cyclopentyl-6-{2-[3-fluoro-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where3-(4-Bromo-2-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (describedbelow), was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzeneof that example.

¹H NMR (CDCl₃): δ 1.55-1.82 (br m, 8H), 1.99 (m, 2H), 2.29 (m, 1H), 2.68(s, 3H), 2.73-2.79 (m, 4H), 3.45 (s, 2H), 7.06 (m, 2H), 7.96 (t 1H,J=7.5 Hz). ESIMS: MH⁺387.20, MH⁻385.20.

Step 1: 3-(4-Bromo-2-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole

A mixture of 4-bromo-2-fluorobenzonitrile (3 g, 15 mmol), hydroxylaminehydrochloride (5.21 g, 75 mmol), potassium carbonate (10.4 g, 75 mmol)in EtOH (50 mL) was refluxed under N₂. After 24 hrs the reaction mixturewas flitered through a glass frit washing with hot EtOH. The filtratewas concentrated to give a white solid. The solid was suspended inpyridine (20 mL) and treated with acetic anhydride (4.24 mL, 45 mmol).The mixture was refluxed for 2 h and then stirred at rt for 15 h. Thereaction mixture was partitioned between 2N HCl and EtOAc. The organiclayer was washed with 1 N HCl, saturated NaHCO₃, brine, dried overNa₂SO₄ and concentrated. The residue was purifed by silica gelchromatography (5% hexanes in EtOAc), to give the title compound as awhite solid, (1.1 g, 29% yield).

¹H NMR (CDCl₃): δ 2.68 (s, 3H), 7.43 (m, 2H), 7.92 (t, 1H, J=7.7 Hz).

Example A(16)4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-N,N-dimethyl-benzamide

The title compound was prepared analogously to Example A(64), where4-Bromo-2-fluoro-N,N-dimethyl-benzamide (described below), wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene.

¹H NMR (CDCl₃): δ 1.42-1.79 (br m, 8H), 1.95 (m, 2H), 2.28 (m, 1H), 2.71(m, 2H), 2.79 (m, 2H), 2.94 (s, 3H), 3.12 (s, 3H), 3.44 (s, 2H), 6.88(d, 1H, J=10.5 Hz), 6.99 (d, 1H, J=7.7 Hz), 7.32 (t, 1H, J=7.3 Hz).Anal. Calcd. For C₂₁H₂₆NO₄F.0.4H₂O: C, 65.91; H, 7.06; N, 3.66. Found:C, 65.84; H, 6.79; N, 3.59.

Step 1: 4-Bromo-2-fluoro-N,N-dimethyl-benzamide

The title compound was prepared as described in Step 1 of Example A(11),where dimethylamine hydrochloride was substituted in place ofmethylamine.

¹H NMR (CDCl₃): δ 2.93 (s, 3H), 3.12 (s, 3H), 7.28 (m, 2H), 7.36 (d, 1H,J=6.4 Hz).

Example A(17)4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-N-ethyl-2-fluoro-benzamide

The title compound was prepared analogously to Example A(64), where4-Bromo-N-ethyl-2-fluoro-benzamide (described below), was substituted inplace of 4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.25 (t, 3H, J=7.1 Hz), 1.45-1.80 (br m, 8H), 1.96 (m,2H), 2.27 (m, 1H), 2.70-2.82 (m, 4H), 3.44 (s, 2H), 3.51 (m, 2H), 6.70(br s, 1H), 6.90 (d, 1H, J=14.1 Hz), 7.05 (d, 1H, J=9.6 Hz), 8.03 (t,1H, J=8.1 Hz). Anal. Calcd. For C₂₁H₂₆NO₄F.0.5H₂O: C, 65.61; H, 7.08; N,3.64. Found: C, 65.76; H, 6.89; N, 3.58.

Step 1: 4-Bromo-N-ethyl-2-fluoro-benzamide

The title compound was prepared as described in Step 1 of Example A(11),where ethylamine hydrochloride was substituted in place of methylamine.

¹H NMR (CDCl₃): δ 1.26 (t, 3H, J=7.4 Hz), 3.65 (m, 2H), 6.63 (br s 1H),7.32 (d, 1H, J=11.3 Hz), 7.42 (d, 1H, J=10.2 Hz), 8.48 (t, 1H, J=8.5Hz).

Example A(18)6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-(4-Bromo-phenyl)-3,5-dimethyl-isoxazole (described below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of thatexample.

¹H NMR (CDCl₃): δ 1.48-1.82 (br m, 8H), 2.02 (m, 2H), 2.26 (s, 3H), 2.32(m, 1H), 2.40 (s, 3H), 2.73 (m, 2H), 2.80 (s, 2H), 3.44 (s, 2H), 7.18(d, 2H, J=8.3 Hz), 7.05 (d, 2H, J=8.3 Hz) Anal. Calcd. ForC₂₃H₂₇NO₄.0.2H₂O: C, 71.74; H, 7.17; N, 3.64. Found: C, 71.77; H, 7.14;N, 3.47.

Step 1: 4-(4-Bromo-phenyl)-3,5-dimethyl-isoxazole

A mixture of 4-bromophenylboronic acid (1 g, 5 mmol),3,5-dimethyl-4-iodoisoxazole (0.93 g, 4.2 mmol),bis(triphenylphospine)palladium(II) chloride (59 mg, 2 mol %), NaHCO₃(1.06 g, 12.6 mmol) in DME (5 mL) and H₂O (5 mL) was heated to 80° C.under N₂ for 18 h. The reaction mixture was partitioned between 1 N HCland EtOAc. The organic layer was washed with saturated NaHCO₃, brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (5% EtOAc in hexanes) to give the title compound as awhite solid (0.9 g, 86%).

¹H NMR (CDCl₃): δ 2.26 (s, 3H), 2.40 (s, 3H), 7.13 (d, 2H, J=8.3 Hz),7.58 (d, 2H, J=8.3 Hz).

Example A(19)6-[2-(1-Acetyl-3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where1-(4-Iodo-3,5-dimethyl-pyrazol-1-yl)-ethanone (described below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene of thatexample.

¹H NMR (CDCl₃): δ 1.46-1.83 (br m, 9H), 2.18 (s, 3H), 2.28-2.44 (m, 4H),2.45 (s, 3H), 2.63 (s, 3H), 2.75 (d, 1H, J=16.0 Hz), 2.83 (d, 1H, J=16.0Hz), 3.37 (d, 1H, J=21.3 Hz), 3.47 (d, 1H, J=21.3 Hz) Anal. Calcd. ForC₁₉H₂₆N₂O₄.0.5H₂O: C, 64.20; H, 7.66; N, 7.88. Found: C, 64.35; H, 7.61;N, 7.56.

Step 1: 1-(4-Iodo-3,5-dimethyl-pyrazol-1-yl)-ethanone

Acetic anhydride (0.51 mL, 5.4 mmol) and triethylamine (0.75 mL, 5.4mmol) were added to a solution of 3,5-dimethyl-4-iodopyrazole (1 g, 4.5mmol) in CH₂Cl₂. After 1 h the reaction mixture was partitioned between1 N HCl and EtOAc. The organic layer was washed with 1 N HCl, saturatedNaHCO₃, brine, dried over Na2SO4, and concentrated to give the titlecompound as a white solid (1 g, 85%).

¹H NMR (CDCl₃): δ 2.27 (s, 3H), 2.60 (s, 3H), 2.66 (s, 3H).

Example A(20)6-Cyclopentyl-6-(5-methoxy-indan-1-ylmethyl)-dihydro-pyran-2,4-dione

The title compound was prepared as described in Example A(13), where1-Cyclopentyl-2-(5-methoxy-indan-1-yl)-ethanone (described in Step 4below), was substituted in place of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹H NMR (CDCl₃): δ 1.24-1.87 (br m, 10H), 2.24-2.56 (m 3H), 2.75-2.93 (m,4H), 3.15-3.31 (m, 1H), 3.42 (s, 2H), 3.78 (s, 3H), 6.73 (d, 1H, J=8.3Hz), 6.78 (s, 1H), 7.02 (d, 1H, J=8.3 Hz).

ESIMS: MH⁺343.10, MH⁻341.10.

Step 1: [3(1″R), 4R]-3-[2′-(5″-Methoxy-1″-indanyl)acetyl]-4-(phenylmethyl)-2-oxazolidinone(A) and [3(1″S), 4R]-3-[2′-(5″-Methoxy-1″-indanyl)acetyl]-4-(phenylmethyl)-2-oxazolidinone(B)

The diastereomers were prepared and separated as described in thefollowing reference: J. Med Chem. 1995, 38, 1386-1396.

Step 2: (5-Methoxy-indan-1-yl)-acetic Acid

2N LiOH (0.82 mL) was added to a solution of [3(1“S),4R]-3-[2′-(5″-Methoxy-1″-indanyl)acetyl]-4-(phenylmethyl)-2-oxazolidinone(0.3 g, 1.64 mmol, from Step 1) dissolved in THF (3 mL). The mixture wasstirred for 2 h under N₂ and then partitioned between 1 N HCl and EtOAc.The organic layer was extracted with 1 N NaOH (×2). The aqueous layerswere made acidic with 2N HCl and extracted with EtOAc (×3). The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to anclear oil (0.14 g, 83%).

¹H NMR (CDCl₃): δ 1.78 (m, 1H), 2.38-2.50 (m, 2H), 2.77-2.95 (m, 3H),3.54 (m, 1H), 3.79 (s, 3H), 6.72 (d, 1H, J=10.6 Hz), 6.78 (s, 1H), 7.10(d, 1H, J=10.6 Hz).

Step 3: (5-Methoxy-indan-1-yl)-thioacetic Acid S-pyridin-2-yl Ester

The title compound was prepared as described in Step 3 of Example A(13),where (5-Methoxy-indan-1-yl)-acetic acid (from Step 2 below) wassubstituted in place of 3-Cyclohex-1-enyl-propionic acid.

¹H NMR (CDCl₃): δ 1.85 (m, 1H), 2.41 (m, 1H), 2.78-2.95 (m, 3H), 3.13(dd, 1H, J=15.6, 5.7 Hz), 3.64 (m, 1H), 3.79 (s, 3H), 6.72 (d, 1H, J=8.3Hz), 6.78 (s, 1H), 7.10 (d, 1H, J=8.3 Hz), 7.31 (m, 1H), 7.65 (m, 1H),7.76 (t, 1H, J=7.8 Hz), 8.63 (d, 1H, J=5.05 Hz).

Step 4: 1-Cyclopentyl-2-(5-methoxy-indan-1-yl)-ethanone

The title compound was prepared as described in Step 4 of Example A(13),where (5-Methoxy-indan-1-yl)-thioacetic acid S-pyridin-2-yl ester (fromStep 3) was substituted in place of 3-Cyclohex-1-enyl-thiopropionic acidS-pyridin-2-yl ester.

¹H NMR (CDCl₃): δ 1.55-1.85 (br m, 9H), 2.39 (m, 1H), 2.60 (dd, 1H,J=17.2, 8.6 Hz), 2.80-2.92 (m, 4H), 3.59 (m, 1H), 3.78 (s, 3H), 6.70 (d,1H, J=8.3 Hz), 6.77 (s, 1H), 7.02 (d, 1H, J=8.3 Hz).

Example A(21)6-Cyclopentyl-6-(5-methoxy-indan-1-ylmethyl)-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(20), where[3(1″R),4R]-3-[2′-(5″-Methoxy-1″-indanyl)acetyl]-4-(phenylmethyl)-2-oxazolidinone(A) (from Step 1 of that example) was substituted in place of [3(1″S),4R]-3-[2′-(5″-Methoxy-1″-indanyl)acetyl]-4-(phenylmethyl)-2-oxazolidinone(B) in Step 2 of that Example.

¹H NMR (CDCl₃): δ 1.24-1.87 (br m, 10H), 2.24-2.41 (m, 2H), 2.51 (m 1H),2.73-2.93 (m, 4H), 3.15-3.31 (m, 1H), 3.42 (s, 2H), 3.78 (s, 3H), 6.73(d, 1H, J=8.3 Hz), 6.78 (s, 1H), 7.02 (d, 1H, J=8.3 Hz). ESIMS:MH⁺343.10, MH⁻341.10.

Example A(22)6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

A mixture of acetic acid4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenylester (0.92 g, 2.47 mmol, from Step 3), potassium carbonate (0.68 g, 4.9mmol) in MeOH (10 mL) was stirred at rt for 1 h. The reaction mixturewas partitioned between 1 N HCl and EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to a yellow oil. The oilwas purified by silica gel chromatography (20% to 40% EtOAc in hexanes)to give the title compound (2.44 g, 59%).

¹H NMR (CDCl₃): δ 1.22 (t, 3H, J=7.6 Hz), 1.43-1.78 (br m, 8H),1.87-2.01 (m, 2H), 2.28 (m, 1H), 2.57-2.63 (m, 4H), 2.76 (s, 2H), 3.42(s, 2H), 4.63 (s, 1H), 6.68 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.1 Hz),6.90 (s, 1H). Anal. Calcd. For C₂₀H₂₆O₄.0.25H₂O: C, 71.72; H, 7.98.Found: C, 71.10; H, 7.99.

Step 1: 4-Bromo-2-ethyl-phenol

Sodium hydroxide (1.4 g, 35 mmol) and hydrazine monohydrate (2.04 mL, 42mmol) were added to a solution of 5′-bromo-2′-hydroxyacetophenone (3 g,14 mmol) dissolved in triethylene glycol (17 mL). The reaction mixturewas heated to 170° C. for 24 h and then partitioned between 1 N HCl andEtOAc. The organic layer was washed with saturated NaHCO₃, brine, driedover Na₂SO₄ and concentrated. The residue was purified by flash silicagel chromatography (0% to 10% EtOAc in hexanes) to give the titlecompound (2.52 g, 90%).

¹H NMR (CDCl₃): δ 1.22 (t, 3H, J=7.5 Hz), 2.60 (q, 2H, J=7.5 Hz), 6.64(d, 1H, J=8.5 Hz), 7.17 (dd, 1H, J=8.5, 2.5 Hz), 7.24 (d, 1H, J=2.5 Hz).

Step 2: Acetic Acid 4-bromo-2-ethyl-phenyl Ester

Acetyl chloride (1.06 mL, 14.9 mmol) followed by triethylamine (2.08 mL,14.9 mmol) were added to a cooled 0° C. solution of4-Bromo-2-ethyl-phenol (2.5 g, 12.4 mmol, from Step 1) dissolved inCH₂Cl₂. The reaction was stirred for 2 hrs and then partitioned between1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO₃,brine, dried over Na₂SO₄ and concentrated to a brown oil. The oil waspurified by silica gel chromatography (0% to 10% EtOAc in hexanes) togive the title compound as a clear oil (2.44 g, 81%).

¹H NMR (CDCl₃): δ 1.19 (t, 3H, J=7.7 Hz), 2.32 (s, 3H), 2.52 (q, 2H,J=7.7 Hz), 6.89 (d, 1H, J=8.5 Hz), 7.32 (dd, 1H, J=8.5, 2.2 Hz), 7.38(d, 1H, J=2.2 Hz).

Step 3: Acetic acid4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenylEster

The title compound was prepared analogously to Example A(64), whereAcetic acid 4-bromo-2-ethyl-phenyl ester (from Step 2) was substitutedin place of 4-bromo-2-fluoro-1-isopropylbenzene of that example.

ESIMS: MH⁺373.20, MH⁻371.20.

Example A(23)6-Ethyl-6-[2-(4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared as described in Example A(13), where1-(4-Methoxy-phenyl)-pentan-3-one (described Step 2 below) wassubstituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹H NMR (CDCl₃): δ 1.01 (t, 3H, J=7.5 Hz), 1.80 (m, 2H), 1.95 (m, 2H),2.66 (m, 2H), 2.72 (s, 2H), 3.42 (s, 2H), 3.79 (s, 3H), 6.83 (d, 2H,J=8.5 Hz), 7.08 (d, 2H, J=8.5 Hz) Anal. Calcd. For C₁₆H₂₀O₄: C, 69.70;H, 7.52. Found: C, 69.54; H, 7.30.

Step 1: N-Methoxy-3-(4-methoxy-phenyl)-N-methyl-propionamide

N,O-dimethylhydroxylamine hydrochloride (5.41 g, 55.5 mmol), EDC (12.77g, 66.6 mmol), followed by triethylamine (17 mL, 122 mmol) were added toa cooled 0° C. solution of 3-(4-methoxyphenyl)propionic acid (10 g, 55.5mmol). The reaction mixture was stirred for 15 h under N₂ and thenconcentrated. The residue was partitioned between 1 N HCl and EtOAc. Theorganic layers were washed with saturated NaHCO₃, brine, dried overNa₂SO₄ and concentrated to an oil. The oil was purified by silica gelchromatography (40% EtOAc in hexanes) to give a clear oil (10.6 g, 85%).

¹H NMR (CDCl₃): δ 2.70 (t, 2H, J=7.5 Hz), 2.91 (t, 2H, J=7.5 Hz), 3.18(s, 3H), 3.61 (s, 3H), 3.79 (s, 3H), 6.83 (d, 2H, J=8.7 Hz), 7.15 (d,2H, J=8.7 Hz).

Step 2: 1-(4-Methoxy-phenyl)-pentan-3-one

Ethylmagnesium bromide (10.8 mL, 10.8 mmol, 1M soln in THF) was added toa cooled −78° C. solution ofN-Methoxy-3-(4-methoxy-phenyl)-N-methyl-propionamide (2 g, 8.96 mmol,from Step 1) dissolved in THF (20 mL). The reaction mixture was stirredfor 60 min. The reaction was quenched with saturated NH₄Cl and extractedwith EtOAc. The organic layer was washed brine, dried over Na₂SO₄ andconcentrated to a clear oil. The residue was purified by silica gelchromatography (5% EtOAc in hexanes) to give the title compound as aclear oil (0.87 g, 50%).

¹H NMR (CDCl₃): δ 1.04 (t, 3H, J=7.4 Hz), 2.39 (q, 2H, J=7.4 Hz), 7.54(m, 2H), 2.84 (m, 2H), 3.78 (s, 3H), 6.82 (d, 2H, J=8.7 Hz), 7.09 (d,2H, J=8.7 Hz).

Example A(24)6-Isobutyl-6-[2-(4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared as described in Example A(13), where1-(4-Methoxy-phenyl)-5-methyl-hexan-3-one (described in Step 2 below)was substituted in place of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹H NMR (CDCl₃): δ 0.99 (d, 3H, J=6.6 Hz), 1.02 (d, 3H, J=6.6 Hz), 1.65(m 2H), 1.88 (m, 1H), 2.01 (m, 2H), 2.64 (m, 2H), 2.74 (s, 2H), 3.24 (s,2H), 3.79 (s, 3H), 6.85 (d, 2H, J=8.5 Hz), 7.08 (d, 2H, J=8.5 Hz).ESIMS: MH⁺305.20, MH⁻303.20.

Step 1: 3-(4-Methoxy-phenyl)-thiopropionic Acid S-pyridin-2-yl Ester

The title compound was prepared as described in Step 3 of Example A(13),where 3-(4-methoxyphenyl)propionic acid was substituted in place of3-Cyclohex-1-enyl-propionic acid.

¹H NMR (CDCl₃): δ 2.98 (s, 4H), 3.76 (s, 3H), 6.83 (d, 2H, J=8.7 Hz),7.13 (d, 2H, J=8.7 Hz), 7.28 (dd, 1H, J=7.5, 5.8 Hz), 7.60 (m, 1H), 7.74(td, 1H, J=7.7, 1.9 Hz), 8.63 (d, 1H, J=5.8 Hz).

Step 2: 1-(4-Methoxy-phenyl)-5-methyl-hexan-3-one

Isobutylmagnesium bromide (0.88 mL, 1.75 mmol, 2M soln in THF) was addedto a cooled −78° C. solution of 3-(4-Methoxy-phenyl)-thiopropionic acidS-pyridin-2-yl ester (0.4 g, 1.46 mmol, from Step 1) dissolved in THF (6mL). The reaction mixture was stirred for 60 min. The reaction wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated to ayellow oil. The residue was purified by silica gel chromatography (5%EtOAc in hexanes) to give the title compound as a clear oil (0.24 g,75%).

¹H NMR (CDCl₃): δ 0.89 (d, 6H, J=6.6 Hz), 2.12 (m, 1H), 2.26 (d, 2H,J=7.0 Hz), 2.60-2.69 (m, 2H), 2.81-2.90 (m, 2H), 3.78 (s, 3H), 6.82 (d,2H, J=8.7 Hz), 7.09 (d, 2H, J=8.7 Hz).

Example A(25)6-[2-(4-Methoxy-phenyl)-ethyl]-6-propyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(13), wherepropylmagnesium chloride was substituted in place ofCyclopentylmagnesium bromide in Step 4 of that Example.

¹H NMR (CDCl₃): δ 0.96 (t, 3H, J=7.2 Hz), 1.44 (m, 2H), 1.70 (m, 2H),1.95 (m, 2H), 2.66 (m, 2H), 2.72 (s, 2H), 3.42 (s, 2H), 3.79 (s, 3H),6.83 (d, 2H, J=8.5 Hz), 7.08 (d, 2H, J=8.5 Hz) Anal. Calcd. ForC₁₇H₂₂O₄.0.2H₂O: C, 69.46; H, 7.68. Found: C, 69.40; H, 7.75.

Example A(26)6-Allyl-6-[2-(4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(23), whereallyl magnesium chloride was substituted in place of ethylmagnesiumbromide in Step 2 of that Example.

¹H NMR (CDCl₃): δ 1.95 (m, 2H), 2.53 (d, 2H, J=7.2 Hz), 2.66-2.74 (m,4H), 3.43 (s, 2H), 3.79 (s, 3H), 5.23 (d, 1H, J=18.5 Hz), 5.27 (d, 1H,J=10.2 Hz), 5.79 (m, 1H), 6.83 (d, 2H, J=8.5 Hz), 7.08 (d, 2H, J=8.5 Hz)Anal. Calcd. For C₁₇H₂₀O₄: C, 70.56; H, 7.07. Found: C, 70.81; H, 6.99.

Example A(27)6-[2-(3-Chloro-4-(6-Methyl-dihydro-pyran-2,4-dione)-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

NaH (60% in mineral oil, 0.14 g, 3.42 mmol) was suspended in THF (5 mL)and cooled to 0° C. Methylacetoacetate (0.19 mL, 1.72 mmol) was slowlyadded via syringe and the reaction mixture stirred 20 min. A solution ofn-BuLi in hexanes (1.6 M, 2.13 mL, 3.42 mmol) was added dropwise and theresulting mixture was stirred an additional 20 min. A solution of3-(4-Acetyl-3-chloro-phenyl)-1-cyclopentyl-propan-1-one (0.16 g, 0.57mmol) from Step 3 below in THF (2 mL) was added dropwise. After stirring1 h, the reaction mixture was quenched with 1 N HCl (10 mL) andextracted with EtOAc (10 mL). The organic phase was dried over Na₂SO₄and evaporated. The crude organic product was then dissolved in 5 mL ofMeOH, and 0.47 grams of finely powdered K₂CO₃ (anhydrous) was added. Theslurry was stirred at 60° C. for 1.5 h, and then concentrated by rotaryevaporation. The residue was dissolved in 10 mL of water and 10 mL ofEtOAc, and acidified with 2N HCl. The aqueous solution was extracted 3times with 5 mL of EtOAc. The organics were combined, and dried withNa₂SO₄. After filtering the residue was purified by flash columnchromatography (40% EtOAc in hexanes) to give the product (0.035 g, 45%)as a white foam.

¹H NMR (CDCl₃): δ 1.44-1.69 (m, 8H), 1.85 (s, 3H), 1.86-1.90 (m, 2H),2.17-2.22 (m, 1H), 2.57-2.63 (m, 2H), 2.69 (d, J=8.1 Hz, 2H), 2.88 (d,J=17.3 Hz, 1H), 3.06 (dd, J=20.5, 3.4 Hz, 1H), 3.29 (d, J=20.5 Hz, 1H),3.36 (s, 2H), 3.86 (dd, J=17.3, 1.7 Hz, 1H), 7.02 (dd, J=8.3, 1.7 Hz,1H), 7.15 (d, J=1.7 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H). Anal. Calcd. ForC₂₄H₂₇ClO₆.0.5H₂O: C, 63.22; H, 6.19. Found: C, 63.45; H, 6.3. ESIMS(MH+): 447.1.

Step 1: 4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl Ester

4-Bromo-2-chlorobenzoic acid (15 g, 63.70 mmol), triphenylphosphine(21.72 g, 82.81 mmol) and 2,2′-dipyridyl disulfide (18.24 g, 82.81 mmol)were combined successively in CH₂Cl₂ (200 mL). The reaction mixture wasstirred 1 h and then loaded directly onto a column for purification byflash chromatography (10% EtOAc in hexanes) to give the product (13.34g, 67%) as a white solid.

¹H NMR (CDCl₃) δ 7.34-7.38 (m, 1H), 7.53 (dd, J=8.3, 1.7 Hz, 1H),7.67-7.85 (m, 4H), 8.68 (d, J=5.6 Hz, 1H). ESIMS (MH+): 329.

Step 2: 1-(4-Bromo-2-chloro-phenyl)-ethanone

4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (1.86 g, 5.66mmol) from Step 1 above was dissolved in dry THF (30 mL) and cooled to−78° C. A solution of methyl magnesium bromide in 75:25 toluene/THF (1.4M, 4.45 mL, 6.23 mmol) was added dropwise. After stirring 35 min, thecooling bath was removed. The reaction mixture was quenched withsaturated 1N HCl and extracted with EtOAc (30 mL). The organic phase waswashed with brine (50 mL), dried over Na₂SO₄ and evaporated. The residuewas purified by flash column chromatography (10% EtOAc in hexanes) togive the product (1.05 g, 80%) as a colorless oil.

¹H NMR (CDCl₃) δ 2.64 (s, 3H), 7.46-7.48 (m, 2H), 7.61 (s, 1H).

Step 3: 3-(4-Acetyl-3-chloro-phenyl)-1-cyclopentyl-propan-1-one

To a magnetically stirring solution of1-(4-Bromo-2-chloro-phenyl)-ethanone (0.92 g, 3.96 mmol) from Step 2above and 1-Cyclopentyl-2-propen-1-ol (0.60 g, 4.75 mmol) in anhydrousN-methylpyrrolidinone (3.0 mL), under argon at room temperature, wasadded sodium bicarbonate (0.40 g, 4.75 mmol) followed by dichlorobis(triphenylphosphine) palladium (II) (84 mg, 0.12 mmol). The resultingmixture was heated to 140° C. in an oil bath and maintained for 4 hours.The resulting dark reaction mixture was cooled to room temperature andpoured into water (50 mL) and extracted with EtOAc (2×25 mL). Theorganics were washed with water (50 mL) and brine (50 mL) then driedover Na₂SO₄, filtered and concentrated. The crude residue was purifiedby flash chromatography (1% through 10% EtOAc in Hexanes) to yield theintermediate ketone as a yellow oil (0.16 g, 16%).

¹H NMR (CDCl₃): δ ?1.55-1.8 (m, 8H), 2.64 (s, 3H), 2.78-2.93 (m, 5H),7.14 (dd, J=8.0, 1.7 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.0 Hz,1H).

Example A(28)6-Cyclopentyl-6-[2-(3-(6-Methyl-dihydro-pyran-2,4-dione)-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where3-Bromo acetophenone was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.17-1.70 (m, 11H), 1.86-1.89 (m, 2H), 2.35-2.45 (m,1H), 2.53-3.35 (m, 10H), 7.05-7.256 (m, 4H). ESIMS (MH+) C₂₄H₂₈O₆: 413.

Example A(29)6-Cyclopentyl-6-{2-[4-(2-methyl-5-oxo-tetrahydro-furan-2-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where5-(3-Bromo-phenyl)-5-methyl-dihydro-furan-2-one (described in Step 1below) was substituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanonein Step 3 of that example.

¹H NMR (CDCl₃): δ 1.58-1.83 (m, 11H), 1.90-2.0 (m, 2H), 2.26-2.33 (m,1H), 2.26-2.27 (m, 6H), 2.78 (s, 2H), 3.42 (s, 2H), 7.14 (d, J=8.2 Hz,2H), 7.29 (d, J=8.2 Hz, 2H). ESIMS (MH+) C₂₃H₂₈O₅: 385.

Step 1: 5-(3-Bromo-phenyl)-5-methyl-dihydro-furan-2-one

To a magnetically stirring solution of 3-(4-Bromobenzoyl)propionic acid(1.0 g, 3.89 mmol) in anhydrous THF (20 mL), under argon at roomtemperature, was added a solution of methyl magnesium bromide in 75:25toluene/THF (1.4 M, 5.8 mL, 8.17 mmol) over a period of 1 h. Theresulting solution was stirred at room temperature for 18 hours. Ice andconc HCl (2 mL) were carefully added and the resulting reaction mixturewas stirred at 80° C. for 8 h. The resultant reaction was cooled to roomtemperature and extracted with EtOAc (2×25 mL). The organics were washedwith water (50 mL) and brine (50 mL) then dried over Na₂SO₄, filteredand concentrated. The crude residue was purified by flash chromatography(40% EtOAc in Hexanes) to yield the intermediate bromide as a clear oil(0.49 g, 50%).

¹H NMR (CDCl₃): δ ?1.70 (m, 3H), 2.39-2.71 (m, 4H), 7.23-7.28 (m, 2H),7.48-7.53 (m, 2H).

Example A(30)6-[2-(3-Chloro-4-(6-Ethyl-dihydro-pyran-2,4-dione)-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where1-(4-Bromo-2-chloro-phenyl)-propan-1-one (described in Step 1 below) wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

¹H NMR (CDCl₃): δ 0.87 (t, J=7.3 Hz, 3H), 1.4-1.7 (m, 8H), 1.92-1.98 (m,2H), 2.09-2.17 (m, 1H), 2.18 (s, 2H), 2.22-2.33 (m, 1H), 2.37-2.47 (m,1H), 2.62-2.78 (m, 2H), 2.95 (d, J=17 Hz, 1H), 3.09 (dd, J=20, 4.7 Hz,1H), 3.33 (d, J=20 Hz, 1H), 3.43 (s, 2H), 3.93 (d, J=17 Hz, 1H), 7.09(d,J=8.1, 1H), 7.22 (s, 1H), 7.88 (d, J=8.1 Hz, 1H). ESIMS (MH−)C₂₅H₂₉ClO₆: 459.

Step 1: 1-(4-Bromo-2-chloro-phenyl)-propan-1-one

The title compound was prepared as described in Step 2 of Example A(27),where ethyl magnesium bromide was substituted for methyl magnesiumbromide. Yield 84%.

¹H NMR (CDCl₃) δ 1.2 (t, J=7.3 Hz, 3H), 2.93 (q, J=7.3 Hz, 2H),7.44-7.64 (m, 3H).

Example A(31)6-[2-(3-Chloro-4-(6-Cyclopropyl-dihydro-pyran-2,4-dione)-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where(4-Bromo-phenyl)-cyclopropyl-methanone was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 0.46-0.61 (m, 2H), 0.83-1.01 (m, 2H), 1.20-1.79 (m,8H), 1.88-2.10 (m, 2H), 2.23-2.42 (m, 2H), 2.62-3.43 (m, 10H), 7.17-7.24(m, 4H). ESIMS (MH−) C₂₆H₃₀O₆: 437.

Example A(32)6-Cyclopentyl-6-[2-(4-cyclopropanecarbonyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where(4-Bromo-phenyl)-cyclopropyl-methanone was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example. Thetitle compound was obtained side product previously described ExampleA(31).

¹H NMR (CDCl₃): δ 1.02-1.06 (m, 2H), 1.21-1.25 (m, 2H), 1.28-1.75 (m,9H), 1.97-2.05 (m, 2H), 2.24-2.30 (m, 1H), 2.64-2.73 (m, 2H), 2.79 (s,2H), 3.44 (s, 2H), 7.25 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H). Anal.Calcd. For C₂₂H₂₆O₄.0.5H₂O: C, 72.70; H, 7.49. Found: C, 72.87; H, 7.38.ESIMS (MH−): 353.

Example A(33)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionicacid methyl ester

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester was substitutedin place of 4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of thatexample.

¹H NMR (CDCl₃): 1.53-1.68 (m, 14H), 1.93-1.98 (m, 2H), 2.25-2.38 (m,1H), 2.63-2.68 (m, 2H) 2.77 (s, 2H), 3.42 (s, 2H), 3.65 (s, 3H),7.09-7.12 (m, 2H), 7.22-7.24 (m, 2H) Anal. Calcd. For C₂₃H₃₀O₅.0.25H₂O:C, 70.65, H, 7.86. Found: C, 70.88, H, 7.82. ESIMS (MH+): 345.2

Example A(34)6-{2-[4-(2-tert-Butyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-phenyl)-2-tert-butyl-[1,3]dioxolane was substituted in placeof 4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 0.94 (s, 9H), 1.5-1.8 (m, 8H), 1.91-2.05 (m, 2H),2.27-2.32 (m, 1H), 2.64-2.70 (m, 2H) 2.77 (s, 2H), 3.42 (s, 2H),3.64-3.68 (m, 2H), 3.92-3.95 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.35 (d,J=8.3 Hz, 2H). Anal. Calcd. For C₂₅H₃₄O₅: C, 72.44; H, 8.27. Found: C,72.65; H, 8.43. ESIMS (MH+): 415.

Example A(35)6-Cyclopentyl-6-{2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-Dione

The title compound was prepared analogously to Example A(27), where(R)1-(4-Bromo-phenyl)-ethanol (described in Step 1 below) wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

¹H NMR (CDCl₃): δ 1.48 (d, J=6.4 Hz, 3H), 1.52-1.79 (m, 8H), 1.95 (q,J=17, 8.5 Hz, 2H), 2.26-2.32 (m, 1H), 2.68 (t, J=8.5 Hz, 2H), 2.78 (s,2H), 3.42 (s, 2H), 4.88 (q, J=13, 6.4 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H),7.31 (d, J=8.1 Hz, 2H). Anal. Calcd. For C₂₀H₂₆O₄.0.5H₂O: C, 70.77; H,8.02. Found: C, 70.37; H, 7.95. ESIMS (MH−): 329.

Step 1: (R)1-(4-Bromo-phenyl)-ethanol

This compound was prepared as described in the following reference:Tetrahedron 2001, 57, 5027-5038.

Example A(36)6-Cyclopentyl-6-{2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where(S)1-(4-Bromo-phenyl)-ethanol (described below) was substituted in placeof 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.48 (d, J=6.4 Hz, 3H), 1.55-1.80 (m, 8H), 1.95 (q,J=17, 8.5 Hz, 2H), 2.23-2.35 (m, 1H), 2.68 (t, J=8.5 Hz, 2H), 2.78 (s,2H), 3.42 (s, 2H), 4.88 (q, J=13, 6.4 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H),7.31 (d, J=8.1 Hz, 2H). Anal. Calcd. For C₂₀H₂₆O₄.0.25H₂O: C, 71.72; H,7.97. Found: C, 71.4; H, 7.95. ESIMS (MH−): 329.

Step 1: (S)1-(4-Bromo-phenyl)-ethanol

This compound was prepared as described in the following reference:Tetrahedron 2001, 57, 5027-5038.

Example A(37)6-Cyclopentyl-6-{2-[4-(2,2-dimethyl-propionyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

To a solution of6-{2-[4-(2-tert-Butyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Example A(34), . (0.173 g) in acetone (1 mL) was added Amberlyst 15(0.05 g). The reaction mixture was stirred at room temperatureovernight, and then filtrated. The solvent was removed under reducedpressure. The residue was purified by flash chromatography (40% EtOAc inHexanes) to yield the product as a white foam (0.04 g, 95%).

¹H NMR (CDCl₃): δ 1.35 (s, 9H), 1.47-1.84 (m, 8H), 1.91-2.03 (m, 2H),2.25-2.34 (m, 1H), 2.72 (t, J=8.0 Hz, 2H), 2.78 (s, 2H), 3.44 (s, 2H),7.18 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H). Anal. Calcd. ForC₂₃H₃₀O₄: C, 74.56; H, 8.16. Found: C, 74.86; H, 8.43. ESIMS (MH+): 371.

Example A(38)N-(1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-ethyl)-acetamide

The title compound was prepared analogously to Example A(64), where(R)N-[1-(4-Bromo-phenyl)-ethyl]-acetamide (described in Step 1 below)was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in Step3 of that example.

¹H NMR (CDCl₃): δ 1.47 (d, J=6.8 Hz, 3H), 1.53-1.82 (m, 8H), 1.91-1.96(m, 2H), 1.98 (s, 3H), 2.24-2.33 (m, 1H), 2.62-2.70 (m, 2H), 2.77 (s,2H), 3.41 (d, J=2.0 Hz, 2H), 5.05-5.13 (m, 1H), 5.66 (d, J=7.5 Hz, 1H),7.11 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H). Anal. Calcd. ForC₂₂H₂₉NO₄.0.25AcOH: C, 69.92; H, 7.82, N, 3.62; Found: C, 69.66; H,7.66, N, 3.75. ESIMS (MH+): 372.

Step 1: (R)N-[1-(4-Bromo-phenyl)-ethyl]-acetamide

To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.52 g,2.59 mmol) in anhydrous CH₂Cl₂ (5 mL) under argon were added aceticanhydride (0.37 mL, 3.89 mmol) and Pyridine (0.31 mL, 3.89 mmol). Theresulting solution was stirred at 25° C. for 3 hrs. The reaction mixturewas quenched with saturated 1 N HCl and extracted with EtOAc (30 mL).The organic phase was washed with brine (50 mL), dried over Na₂SO₄ andevaporated. The residue was purified by flash column chromatography (80%EtOAc in hexanes) to give the product (0.62 g, 100%) as a white solid.

¹H NMR (CDCl₃) δ: 1.46 (d, J=7.0 Hz, 3H), 1.99 (s, 3H), 5.03-5.12 (m,1H), 5.68 (brs, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H).ESIMS (MNa+): 264.

Example A(39)N-(1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-ethyl)-malonamicacid ethyl ester

The title compound was prepared analogously to Example A(64), where(R)N-[1-(4-Bromo-phenyl)-ethyl]-malonamic acid ethyl ester (described inStep 1 below) was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.29 (t, J=7.7 Hz, 3H), 1.48 (d, J=7.1 Hz, 3H),1.59-1.78 (m, 8H), 1.89-2.05 (m, 2H), 2.25-2.30 (m, 1H), 2.64-2.68 (m,2H), 2.77 (s, 2H), 3.31 (d, J=3.4 Hz, 2H), 3.42 (s, 2H), 4.19 (q, J=7.1Hz, 2H), 5.09-5.14 (m, 1H), 7.11 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz,2H), 7.49 (d, J=7.3 Hz, 1H). Anal. Calcd. For C₂₅H₃₃NO₆.1.0AcOH.0.5H₂O:C, 63.27; H, 7.47, N, 2.73; Found: C, 63.30; H, 7.19, N, 2.91. ESIMS(MH+): 444.

Step 1: (R)N-[1-(4-Bromo-phenyl)-ethyl]-malonamic Acid Ethyl Ester

To a magnetically stirred solution of(R)-(+)-1-(4-bromophenyl)ethylamine (0.51 g, 2.55 mmol) in anhydrousCH₂Cl₂ under argon and cooled to 0° C., were added ethyl hydrogenmalonate (0.4 g, 3.06 mmol) EDC.HCl (0.58 g, 3.06 mmol) and HOBt (0.41g, 3.06 mmol). The resulting solution was stirred at 25° C. overnight.CH₂Cl₂ was evaporate and residue partitioned between EtOAC and 1 N HCl.The organic layer was washed with H₂O, brine and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography (40% EtOAc in hexanes) to provide the desiredproduct (0.57 g, 71%) as a white solid.

¹H NMR (CDCl₃): δ 1.29 (t, J=7.2 Hz, 3H), 1.48 (d, J=7.0 Hz, 3H), 3.31(d, J=1.9 Hz, 2H), 4.2 (q, J=7.2 Hz, 2H), 5.06-5.14 (m, 1H), 7.20 (d,J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.48 (brs, 1H). ESIMS (MH+): 315.

Example A(40)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-cyclopropanecarbonitrile

The title compound was prepared analogously to Example A(64), where1-(4-Bromophenyl)cyclopropane carbonitrile was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.35-1.39 (m, 2H), 1.5-1.87 (m, 10H), 1.87-2.00 (m,2H), 2.22-2.33 (m, 1H), 2.67 (t, J=8.4 Hz, 2H), 2.77 (s, 2H), 3.42 (d,J=1.5 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H). Anal.Calcd. For C₂₂H₂₅NO₃: C, 75.19; H, 7.17, N, 3.99. Found: C, 75.38; H,7.40, N, 4.04. ESIMS (MH−): 352.

Example A(41)1-(1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-ethyl)-3-methyl-urea

The title compound was prepared analogously to Example A(64), where (R)1-[1-(4-Bromo-phenyl)-ethyl]-3-methyl-urea (described in Step 1 below)was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in Step3 of that example.

¹H NMR (DMSO-d₆): δ 1.09 (d, J=6.8 Hz, 3H), 1.32-1.47 (m, 8H), 1.69-1.73(m, 2H), 1.91 (s, 3H), 2.12-2.18 (m, 1H), 2.33-2.42 (m, 2H), 3.16 (s,2H), 4.45-4.57 (m, 1H), 4.80 (s, 1H), 5.4 (q, J=4.3 Hz, 1H), 6.10 (d,J=8.3 Hz, 1H), 6.93 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.1 Hz, 2H), 11.17 (s,1H). ESIMS (MH−) C₂₂H₃₀N₂O₄: 385.

Step 1: (R) 1-[1-(4-Bromo-phenyl)ethyl]-3-methyl-urea

To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g,2.49 mmol) in anhydrous CH₂Cl₂ was added methyl isocyanate (0.15 mL,2.49 mmol). The resulting solution was stirred at 25° C. overnight.CH₂Cl₂ was evaporate and residue partitioned between EtOAC and 1 N HCl.The organic layer was washed with H₂O, brine and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography (80% EtOAc in hexanes) to provide the desiredproduct (0.60 g, 94%) as a white solid.

¹H NMR (CDCl₃) δ: 1.42 (d, J=7.0 Hz, 3H), 2.72 (d, J=4.9 Hz, 3H), 4.25(brs, 1H), 4.73 (brs, 1H), 4.74-4.81 (m, 1H), 7.20 (d, J=8.3 Hz, 2H),7.45 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 258.

Example A(42)N-(1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-ethyl)-methanesulfonamide

The title compound was prepared analogously to Example A(64), where(R)N-[1-(4-Bromo-phenyl)-ethyl]-methanesulfonamide (described in Step 1below) was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzenein Step 3 of that example.

¹H NMR (CDCl₃): δ 1.52 (d, J=7.2 Hz, 3H), 1.58-1.72 (m, 8H), 1.93-2.05(m, 2H), 2.27-2.30 (m, 2H), 2.66 (s, 3H), 2.45-2.46 (m, 1H), 2.78 (s,2H), 3.42 (d, J=2.7 Hz, 2H), 4.54 (d, J=3.0 Hz, 1H), 4.60-4.65 (m, 1H),7.15 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H). Anal. Calcd. ForC₂₁H₂₉NO₅S: C, 61.89; H, 7.17, N, 3.44; Found: C, 61.94; H, 7.40, N,3.59. ESIMS (MH−): 406.

Step 1: (R)N-[1-(4-Bromo-phenyl)-ethyl]-methanesulfonamide

To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g,2.49 mmol), in anhydrous CH₂Cl₂ (5 mL) under argon were added methanesulfonyl chloride (0.23 mL, 2.99 mmol) and Pyridine (0.30 mL, 3.73mmol). The resulting solution was stirred at 25° C. for 3 hrs. Thereaction mixture was quenched with 1 N HCl and extracted with EtOAc (30mL). The organic phase was washed with brine (50 mL), dried over Na₂SO₄and evaporated. The residue was purified by flash column chromatography(80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a whitesolid.

¹H NMR (CDCl₃) δ: 1.52 (d, J=6.8 Hz, 3H), 2.67 (s, 3H), 4.61-4.72 (m,2H), 7.24 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 279.

Example A(43) 5-Methyl-isoxazole-3-carboxylic acid(1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-ethyl)-amide

The title compound was prepared analogously to Example A(64), where(R)-5-Methyl-isoxazole-3-carboxylic acid[1-(4-bromo-phenyl)-ethyl]-amide (described in Step 1 below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.56 (d, J=6.0 Hz, 3H), 1.58-1.89 (m, 8H), 1.91-2.05(m, 2H), 2.25-2.29 (m, 1H), 2.47 (s, 3H), 2.64-2.67 (m, 2H), 2.77 (s,2H), 3.42 (s, 2H), 5.19-5.25 (m, 1H), 6.42 (s, 1H), 6.99 (d, J=3.0 Hz,1H), 7.13 (d, J=6.0 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H). Anal. Calcd. ForC₂₅H₃₀N₂O₅: C, 68.47; H, 6.90, N, 6.39; Found: C, 68.70; H, 7.10, N,6.65. ESIMS (MH+): 439.

Step 1: (R)-5-Methyl-isoxazole-3-carboxylic Acid[1-(4-bromo-phenyl)-ethyl]-amide

The title compound was prepared as described in Step 1 of Example A(39),where 5-methylisoxazole-3-carboxylic acid was substituted for ethylhydrogen malonate. Yield 84%.

Example A(44)6-(2-Cyclohexyl-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where3-Cyclohexyl-1-cyclopentyl-propan-1-one (from Step 2 below), wassubstituted in place of3-(4-Acetyl-3-chloro-phenyl)-1-cyclopentyl-propan-1-one of that example.

¹H NMR (CDCl₃): δ 1.17-2.17 (m, 24H), 2.69 (s, 2H), 3.39 (s, 2H) Anal.Calcd. For C₁₈H₂₈O₃: C, 73.93; H, 9.65. Found: C, 74.01; H, 9.80. ESIMS(MH+): 293.

Step 1: 3-Cyclohexyl-thiopropionic Acid S-pyridin-2-yl Ester

3-Cyclohexylpropionic acid (1 g, 6.40 mmol), triphenylphosphine (2.18 g,8.32 mmol) and 2,2′-dipyridyl disulfide (1.83 g, 8.32 mmol) werecombined successively in CH₂Cl₂ (20 mL). The reaction mixture wasstirred 1 h and then loaded directly onto a column for purification byflash chromatography (20% EtOAc in hexanes) to give a residue. Thisresidue was washed with hexanes (20 mL) and the solid, partiallycrystalline material was collected by filtration and air dried to givethe product (1.43 g, 90%) as a white solid.

¹H NMR (CDCl₃): δ: 0.91-1.52 (m, 13H), 2.1 (t, J=7.5 Hz, 2H), 7.21-7.26(m, 1H), 7.53-7.56 (m, 1H), 7.65-7.70 (m, 1H), 8.54-8.56 (m, 1H).

Step 2: 3-Cyclohexyl-1-cyclopentyl-propan-1-one

3-Cyclohexyl-thiopropionic acid S-pyridin-2-yl ester (1.43 g, 5.74 mmol)from Step 1 above was dissolved in dry THF (28 mL) and cooled to −78° C.A solution of cyclopentylmagnesium bromide in Et₂O (2.0 M, 3.01 mL, 6.02mmol) was added dropwise. After stirring 1 h, the cooling bath wasremoved. The reaction mixture was quenched with 1 N HCl and extractedwith EtOAc (100 mL). The organic phase was washed with brine (50 mL),dried over Na₂SO₄ and evaporated. The residue was purified by flashcolumn chromatography (1% EtOAc in hexanes) to give the product (0.99 g,83%) as clear oil.

¹H NMR (CDCl₃) δ: 0.82-1.84 (m, 21H), 2.42-2.47 (m, 2H), 2.82-2.92 (m,1H).

Example A(45)4′-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-biphenyl-3-carbonitrile

The title compound was prepared analogously to Example A(27), where4′-Bromo-biphenyl-3-carbonitrile (described in Step 1 below), wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

¹H NMR (CDCl₃): δ 1.59-1.81 (m, 8H), 1.99-2.05 (m, 2H), 2.30-2.33 (m,1H), 2.72-2.79 (m, 2H), 2.8 (s, 2H), 3.45 (s, 2H), 7.26 (d, J=7.4 Hz,2H), 7.46-7.56 (s, 3H), 7.61-7.64 (m, 1H), 7.77-7.8 (m, 1H), 7.83-7.85(m, 1H). Anal. Calcd. For C₂₅H₂₅O₃: C, 77.49; H, 6.50, N, 3.61. Found:C, 77.63; H, 6.75, N, 3.80.

ESIMS (MH+): 388. IR (cm⁻¹): 3397, 2955, 2229, 1659, 1227.

Step 1: 4′-Bromo-biphenyl-3-carbonitrile

To a magnetically stirring solution of 3-cyanophenyl boronic acid (0.62g, 4.24 mmol) and 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in anhydrousDMF (7.0 mL), under argon at room temperature, was added 2M sodiumcarbonate solution (7.0 mL) followed by Pd(PPh₃)₄ (0.21 g, 0.18 mmol).The resulting mixture was heated to 75° C. overnight. The resulting darkreaction mixture was cooled to room temperature filtered to remove thesolids and the resultant filtrate was poured into water (50 mL) andextracted with EtOAc (2×25 mL). The organics were washed with water (50mL) and brine (50 mL) then dried over Na₂SO₄, filtered and concentrated.The crude residue was purified by flash chromatography (5% EtOAc inHexanes) to yield the intermediate bromide as a white solid (0.36 g,33%).

¹H NMR (CDCl₃): δ ¹H NMR (CDCl₃) δ: 7.43 (d, J=7.4 Hz, 2H), 7.53-7.67(m, 4H), 7.76-7.84 (m, 2H).

Example A(46)2-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-benzonitrile

The title compound was prepared analogously to Example A(27), where2-bromobenzonitrile was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.59-1.81 (m, 8H), 1.99-2.05 (m, 2H), 2.30-2.33 (m,1H), 2.72-2.77 (m, 2H), 2.81 (s, 2H), 3.48 (s, 2H), 7.26-7.85 (m, 4H)Anal. Calcd. For C₁₉H₂₁NO₃: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.17;H, 6.84; N, 4.42. ESIMS (MH−): 310.

Example A(47)6-Cyclopentyl-6-(2-naphthalen-2-yl-ethyl)-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-bromonaphatalene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.5-1.9 (m, 8H), 1.93 (m, 2H), 2.24 (m, 1H), 2.9 (s,2H), 2.90 (t, J=8.4 Hz, 2H), 3.5 (s, 2H), 7.2 (m, 1H), 7.4 (m, 2H), 7.6(s, 1H), 7.8 (m 3H). Anal. Calcd. For C₂₂H₂₄O₃: C, 78.54; H, 7.19.Found: C, 78.70; H, 7.25. ESIMS (MH+): 337.

Example A(48)6-Cyclopentyl-6{2-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-(4-bromophenoxyl) tetrahydro 2H-pyran was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.28-1.98 (m, 16H), 2.2-2.31 (m, 1H), 2.62 (t, J=8.6,2H), 2.76 (s, 2H), 3.42 (s, 2H), 3.55-3.61 (m, 1H), 3.86-3.94 (m, 1H),5.38 (t, J=3.1, 1H), 6.97 (d, J=8.7, 2H), 7.05 (d, J=8.7, 2H). Anal.Calcd. For C₂₃H₃₀O₅.0.5H₂O: C, 69.85; H, 7.90. Found: C, 70.19; H, 8.01.ESIMS (MNa+): 409.

Example A(49)2{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-N-methyl-isobutyramide

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-phenyl)-N-methyl-isobutyramide (described in Step 1 below),was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in Step3 of that example.

¹H NMR (CDCl₃): δ 1.55 (s, 6H); 1.59-1.73 (m, 8H), 1.94-2.05 (m, 2H),2.28-2.35 (m, 1H), 2.67-2.69 (m, 2H), 2.76 (s, 3H), 2.76 (s, 2H), 3.40(s, 2H), 5.2 (brs, 1H), 7.14 (d, J=8.3, 2H), 7.30 (d, J=8.3, 2H). Anal.Calcd. For C₂₃H₃₁NO₄: C, 71.66; H, 8.10, N, 3.63. Found: C, 71.80; H,8.35, N, 3.77. ESIMS (MH+): 386.

Step 1: 2-(4-Bromo-phenyl)-N-methyl-isobutyramide

The title compound was prepared as described in Step 1 of Example A(39),where 2-(4-bromophenyl)-2-methyl propionic acid was substituted forethyl hydrogen malonate and methyl amine was substituted instead of(R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 84%.

¹H NMR (CDCl₃) δ: 1.55 (s, 6H), 2.72 (d, J=4.6 Hz, 3H), 5.15 (brs, 1H),7.22-7.26 (m, 2H), 7.46-7.50 (m, 2H).

Example A(50)6-Cyclopentyl-6-{2-[4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where2-(4-bromophenyl)-5-phenyl-1,2,3-oxadiazole was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.44-1.82 (m, 8H), 1.99-2.05 (m, 2H), 2.30-2.34 (m,1H), 2.76-2.79 (m, 2H), 2.81 (s, 2H), 3.46 (s, 2H), 7.32 (d, J=8.3, 2H),7.51-7.58 (m, 3H), 8.07 (d, J=8.3, 2H), 8.13-8.16 (m, 2H). Anal. Calcd.For C₂₆H₂₆N₂O₄.0.5H₂O: C, 71.05; H, 6.19, N, 6.37. Found: C, 71.32; H,6.06, N, 6.45. ESIMS (MH+): 431.

Example A(51)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl)-N-ethyl-isobutyramide

The title compound was prepared analogously to Example A(64), where2-(4-Bromo-phenyl)-N-ethyl-isobutyramide (described in Step 1 below) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.01 (t, J=7.2, 3H), 1.54 (s, 6H); 1.63-1.7 (m, 8H),1.92-1.99 (m, 2H), 2.29-2.32 (m, 1H), 2.69 (t, J=8.3, 2H), 2.76 (s, 2H),3.21 (q, J=7.2, 5.28, 2H), 3.40 (s, 2H), 5.4 (brs, 1H), 7.12 (d, J=8.3,2H), 7.28 (d, J=8.3, 2H). Anal. Calcd. For C₂₄H₃₃NO₄: C, 72.15; H, 8.32,N, 3.51. Found: C, 72.40; H, 8.60, N, 3.77. ESIMS (MH+): 400.

Step 1: 2-(4-Bromo-phenyl)-N-ethyl-isobutyramide

The title compound was prepared as described in Step 1 of Example A(39),where 2-(4-bromophenyl)-2-methyl propionic acid was substituted forethyl hydrogen malonate and ethyl amine was substituted for(R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 82%.

¹H NMR (CDCl₃) δ: 1.01 (t, J=5.3 Hz, 3H), 1.55 (s, 6H),), 3.2 (q, J=7.0,5.3, 2H), 5.15 (brs, 11), 7.22-7.26 (m, 2H), 7.46-7.50 (m, 2H).

Example A(52)6-4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenoxy}-6-methyl-3,5-dioxo-heptanoicacid methyl ester

The title compound was prepared analogously to Example A(27), where2-(4-Bromo-2-fluoro-phenoxy)-2-methyl-propionic acid methyl ester(described in Step 1 below) was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.48 (s, 3H); 1.55 (s, 3H), 1.58-1.77 (m, 8H),1.90-1.97 (m, 2H), 2.22-2.30 (m, 1H), 2.60-2.88 (m, 6H), 3.39 (s, 2H),3.43 (s, 1H), 3.72 (s, 1H), 3.75 (s, 3H), 6.76-7.01 (m, 3H). ESIMS(MH+): 505.

Step 1: 2-(4-Bromo-2-fluoro-phenoxy)-2-methyl-propionic Acid MethylEster

To a solution of 4-Bromo-2-fluorophenol (1 g, 5.24 mmol) and methyl□-bromobutyrate (1.89 g, 10.47 mmol) in DMF (20 mL) was added K₂CO₃ (3.6g, 26 mmol). The resultant slurry was heated to 100° C. under argon for12 h. DMF was evaporate and residue partitioned between EtOAC and 1 NHCl. The organic layer was washed with H₂O, and brine then dried overNa₂SO₄. The solvent was removed in vacuo and the residue was purified byflash column chromatography (10% EtOAc in hexanes) to provide thedesired product (1.17 g, 77%) as a white solid.

¹H NMR (CDCl₃) δ: 1.57 (s, 6H), 3.79 (s, 3H),), 6.86 (t, J=8.7, 1H),7.12-7.16 (m, 1H), 7.23-7.27 (m, 1H).

Example A(53)2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenoxy}-2-methyl-propionicacid methyl ester

REVERSE ADDITION MODIFICATION: NaH (60% in mineral oil, 0.13 g, 3.13mmol) was suspended in THF (10 mL) and cooled to 0° C.Methylacetoacetate (0.19 mL, 1.72 mmol) was slowly added via syringe andthe reaction mixture stirred 20 min. A solution of n-BuLi in hexanes(1.6 M, 1.95 mL, 3.13 mmol) was added dropwise and the resulting mixturewas stirred an additional 20 min. The resultant slurry was added viacanula to a solution of2-[2-Chloro-4-(3-cyclopentyl-3-oxo-propyl)-phenoxy]-2-methyl-propionicacid methyl ester (0.85 g, 2.41 mmol) from Step 1 below in THF (2 mL)pre-cooled to 0° C. After stirring 1 h, the reaction mixture wasquenched with 1N HCl (10 mL) and extracted with EtOAc (10 mL). Theorganic phase was dried over Na₂SO₄ and evaporated. The crude organicproduct was then dissolved in 5 mL of MeOH, and 0.67 grams of finelypowdered K₂CO₃ (anhydrous) was added. The slurry was stirred at 60° C.for 1.5 h, and then concentrated by rotary evaporation. The residue wasdissolved in 10 mL of water and 10 mL of EtOAc, and acidified with 2NHCl. The aqueous solution was extracted 3 times with 5 mL of EtOAc. Theorganics were combined, and dried with Na₂SO₄. After filtering theresidue was purified by flash column chromatography (50% EtOAc inhexanes) to give the product (0.22 g, 25%) as a white foam.

¹H NMR (CDCl₃): δ 1.60 (s, 6H); 1.55-1.81 (m, 8H), 1.88-1.96 (m, 2H),2.23-2.26 (m, 1H), 2.60 (t, J 7.9, 2H), 2.75 (d, J=2.6, 2H), 3.43 (s,2H), 3.80 (s, 3H), 6.79 (d, J=8.3, 1H), 6.90 (d, J=2, 1H), 7.15 (d, J=2,1H). Anal. Calcd. For C₂₃H₂₉ClO₆: C, 63.23; H, 6.69. Found: C, 63.20; H,6.95. ESIMS (MH+): 437.

Step 1:2-[2-Chloro-4-(3-cyclopentyl-3-oxo-propyl)-phenoxy]-2-methyl-propionicAcid Methyl Ester

The title compound was prepared analogously to Step 1 from exampleA(52), where 3-(3-Chloro-4-hydroxy-phenyl)-1-cyclopentyl-propan-1-onewas substituted for 4-Bromo-2-fluorophenol in Step 1 of that example.Yield 74%.

¹H NMR (CDCl₃) δ: 1.59 (s, 6H), 1.61-1.80 (m, 9H), 2.70-2.84 (m, 4H),3.79 (s, 3H),), 6.78 (d, J=8.4, 11), 6.93 (dd, J=8.4, 2.3, 1H), 7.18 (d,J=2.3, 1H).

Example A(54)2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenoxy)-aceticAcid

The title compound was prepared analogously to Example A(53), where[2-Chloro-4-(3-cyclopentyl-3-oxo-propyl)-phenoxy]-acetic acid methylester (described in Step 1 below) was substituted in place of2-[2-Chloro-4-(3-cyclopentyl-3-oxo-propyl)-phenoxy]-2-methyl-propionicacid methyl ester) of that example.

¹H NMR (CDCl₃): δ 1.47-1.74 (s, 8H); 1.89-1.96 (m, 2H), 2.23-2.29 (m,1H), 2.62 (t, 1 J=8.3, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 4.72 (s, 2H),6.81 (d, J=8.3, 1H), 6.98 (dd, J=8.3, 2.3, 1H), 7.18 (d, J=2.3, 1H).

ESIMS (MH+): 395.

Step 1: [2-Chloro-4-(3-cyclopentyl-3-oxo-propyl)-phenoxy]-acetic AcidMethyl Ester

The title compound was prepared analogously to Step 1 from ExampleA(52), where 3-(3-Chloro-4-hydroxy-phenyl)-1-cyclopentyl-propan-1-onewas substituted for 4-Bromo-2-fluorophenol and methyl bromo acetate wassubstituted for methyl □-bromobutyrate in Step 1 of that example. Yield78%.

¹H NMR (CDCl₃) δ: 1.55-1.77 (m, 9H), 2.70-2.85 (m, 4H), 3.80 (s, 3H),),4.68 (sm 2H), 6.75 (d, J=8.5, 1H), 7.0 (dd, J=8.5, 2.2, 1H), 7.21 (d,J=2.2, 1H).

Example A(55)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenoxy}-2-methyl-propionicacid methyl ester

The title compound was prepared analogously to Example A(27), where2-(4-Bromo-2-fluoro-phenoxy)-2-methyl-propionic acid methyl ester(described in Step 1 of Example A(52), was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.56 (s, 6H); 1.58-1.73 (m, 8H), 1.90-1.97 (m, 2H),2.20-2.23 (m, 1H), 2.62 (t, J=8.1, 2H), 2.75 (s, 2H), 3.43 (s, 2H), 3.79(s, 3H), 6.80-6.92 (m, 2H), 7.32-7.38 (m, 1H). Anal. Calcd. ForC₂₃H₂₉FO₆.0.5H₂O: C, 65.00; H, 7.00. Found: C, 65.30; H, 7.32. ESIMS(MH+): 421.

Example A(56)6-Cyclopentyl-6-(2-{4-[1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-phenyl}-ethyl)-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where3-[1-(4-Bromo-phenyl)-1-methyl-ethyl]-5-methyl-[1,2,4]oxadiazole(described in Step 1 below) was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example. H₁₁NMR(CDCl₃): δ 1.59-1.78 (m 9H); 1.85-1.98 (m, 2H), 2.18 (s, 6H), 2.20-2.31(m, 1H), 2.52 (s, 3H), 2.61-2.67 (m, 1H), 2.77 (s, 2H), 3.42 (s, 2H),7.09 (d, J=8.3, 2H), 7.24 (d, J=8.3, 2H). ESIMS (MH+): 411.

Step 1: 3-[1-(4-Bromo-phenyl)-1-methyl-ethyl]-5-methyl-[1,2,4]oxadiazole

To a solution of 2-(4-bromophenyl)-2-methylpropionitrile (3 g, 13.38mmol)) in EtOH (40 mL) was added hydroxylamine HCl (4.65 g, 66.93 mmol)and K₂CO₃ (9.25 g, 66.93 mmol). The reaction mixture was stirred at roomtemperature overnight. The resultant white precipitate was eliminated byfiltration and the filtrate was concentrated to a yellow oil which wasdissolved in pyridine (16 mL). Acetic anhydride (3.79 mL, 40.14 mol) wasadded and the reaction was stirred to reflux for 2 hours. The solutionwas quenched with 2N HCl (50 mL) and extracted 3 times with EtOAc (20mL). The organics were combined, and dried with Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by flashchromatography (40% EtOAc in Hexanes) to yield the product as a whitefoam (0.88 g, 30%).

¹H NMR (CDCl₃): δ 1.71 (s, 6H); 2.53 (s, 3H), 7.18-7.54 (m, 4H).

Example A(57)6-(4-Cyclohexyl-butyl)-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(44), where4-Cyclohexyl-butyric acid was substituted in place of3-Cyclohexylpropionic acid in Step 1 of that example.

¹H NMR (CDCl₃): δ 0.75-1.9 (m, 26H), 2-2.25 (m, 2H), 2.69 (s, 2H), 3.40(s, 2H). Anal. Calcd. For C₂₀H₃₂O₃: C, 74.96; H, 10.06. Found: C, 75.04;H, 10.34. ESIMS (MH+): 321.

Example A(58)6-Cyclopentyl-6-[2-(4-difluoromethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-(difluoromethoxy) bromobenzene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.5-1.9 (m, 8H), 1.93 (m, 2H), 2.24 (m, 2H), 2.9 (s,2H), 2.93 (t, J=8.4 Hz, 2H), 3.2 (s, 2H), 7.2 (d, J=8.3, 2H), 7.4 (d,J=8.3, 2H). ESIMS (MH+): 353.

Example A(59)6-Cyclopentyl-6-[2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where6-bromo-2,2,3,3-tetrafluoro-1,4-benzodioxene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.63-1.75 (m, 8H), 1.90-1.97 (m, 2H), 2.24-2.29 (m,1H), 2.64-2.71 (m, 2H), 2.77 (d, J=4.9, 2H), 3.43 (d, J=2.4, 2H),6.90-6.97 (m, 2H), 7.07 (d, J=7.5, 1H). Anal. Calcd. For C₂₀H₂O F₄O₅: C,57.69; H, 4.84. Found: C, 57.76; H, 4.90. ESIMS (MH+): 417.

Example A(60)6-Cyclopentyl-6-[2-(4-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(44), where3-(4-Propoxy-phenyl)-propionic acid (described in Step 1 below) wassubstituted in place of 3-Cyclohexylpropionic acid in Step 3 of thatexample of that example.

¹H NMR (dmso-d₆): δ 0.96 (t, J=7.4, 3H), 1.34-1.73 (m, 10H), 1.87-1.90(m, 2H), 2.25-2.35 (m, 1H), 2.46-2.55 (m, 2H), 3.33 (s, 2H), 3.87 (t,J=6.5, 2H), 4.98 (s, 2H), 6.82 (d, J=8.4, 2H), 7.07 (d, J=8.4, 2H).Anal. Calcd. For C₂₁H₂₈O₄: C, 73.23; H, 8.19. Found: C, 73.24; H, 8.30.ESIMS (MH+): 345.

Step 1: 3-(4-Propoxy-phenyl)-propionic Acid

To a solution of methyl 3-(hydroxyphenyl)propionate (15 g, 83.24 mmol)and iodopropane (12.14 mL, 124.5 mmol) in DMF (80 mL) was added K₂CO₃(34 g, 249.7 mmol). The resultant slurry was stirred vigorously andheated to 60° C. under argon for 12 h. DMF was evaporated and residuepartitioned between EtOAC and 1 N HCl. The organic layer was washed withH₂O, and brine then dried over Na₂SO₄. The solvent was removed in vacuoand the residue was purified by flash column chromatography (10% EtOAcin hexanes) to provide the desired product (17 g, 98%) as a clear oil.The resultat oil was dissolved in THF (150 mL), and 2M NaOH (68 mL) wasadded. The reaction was stirred overnight at room temperature. THF wasevaporated and residue acidified with concentrated HCl and extracted 3times with EtOAC, (100 mL). The organic layer was washed with H₂O, driedover Na₂SO₄ and concentrated to a white solid which was recrystalizedfrom hexanes to provide the desired product (14.06 g 82%).

¹H NMR (CDCl₃) δ: 1.04 (t, J=7.2, 3H), 1.76-1.85 (m, 2H), 2.64 (t,J=8.1, 2H), 2.90 (t, J=8.1, 2H), 3.89 (t, J=6.6, 2H), 6.82 (d, J=8.6,2H), 7.10 (d, J=8.6, 2H).

Example A(61)6-[2-(2-acetyl-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dine

The title compound was prepared analogously to Example A(64), where1-(2-bromo-5-methoxyphenyl)ethanone was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene.

¹H NMR (300 MHz, CDCL₃) δ ppm 1.41 (m, 1H), 1.61 (m, 5H), 1.78 (m, 2H),1.88 (ddd, J=14.0, 12.2, 5.0 Hz, 1H), 2.02 (td, J=12.25 4.5 Hz, 1H),2.36 (m, 1H), 2.56 (s, 3H), 2.72 (td, J=12.2, 4.7 Hz, 1H), 2.76 (d,J=16.4 Hz, 1H), 2.84 (d, J=16.4 Hz, 1H), 2.92 (td, J=12.2, 4.6 Hz, 1H),3.42 (d, J=21.2 Hz, 1H), 3.62 (d, J=21.2 Hz, 1H), 3.83 (s, 3H), 6.97(dd, J=8.5, 2.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H).HRMS calcd. For C₂₁H₂₆O₅Na (M+Na): 381.1672. Found: 381.1666.

Example A(62)6-cyclopentyl-6-[2-(4-methoxy-2-propionylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(64), where1-(2-bromo-5-ethoxyphenyl)ethanone was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene.

¹H NMR (300 MHz, CDCl₃) δ ppm 1.17 (t, J=7.2 Hz, 3H), 1.40 (m, 1H), 1.73(m, 8H), 2.03 (m, 1H), 2.35 (m, 1H), 2.68 (td, J=12.3, 4.8 Hz, 1H), 2.79(m, 2H), 2.89 (m, 3H), 3.42 (d, J=21.1 Hz, 1H), 3.63 (d, J=21.1 Hz, 1H),3.82 (s, 3H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.16(d, J=2.7 Hz, 1H). Anal. Calcd. For C₂₂H₂₈O₅: C, 70.94; H, 7.58; 0,21.48. Found: C, 70.72; H, 7.60; 0, 21.33.

Example A(63)6-[2-(3-chloro-4-isopropylphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(82), where4-bromo-2-chloro-1-isopropylbenzene was substituted in place of2-Bromopyridine.

¹H NMR (300 MHz, CDCl₃) δ: 1.22 (d, J=6.78 Hz, 6H), 1.60-1.80 (m, 8H),1.91-1.98 (m, 2H), 2.22-2.30 (m, 1H), 2.59-2.66 (m, 2H), 2.76 (s, 2H),3.31-3.38 (m, 1H), 3.43 (s, 2H), 7.01 (dd, J=8.01, 1.79 Hz, 1 H), 7.12(d, J=1.88 Hz, 1H), 7.20 (d, J=7.91 Hz, 1H). HRMS calcd forC₂₁H₂₇ClO₃Na: 385.1541. Found: 385.1543.

Example A(64)6-cyclopentyl-6-[2-(3-fluoro-4-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

6-[2-cyclopentyl-4-(3-fluoro-4-isopropylphenyl)-2-hydroxybut-3-ynyl]-2,2-dimethyl-4H-1,3-dioxin-4-one(3.83 g, 9.6 mmol, described in Step 3 below) dissolved in anhydrousMeOH (45 mL) was added Pd(OH)₂ (1.26 g). The reaction was stirred underH₂ (1 atm) for 12 hours. The mixture was filtered through a pad ofcelite. The solvent was removed in vacuo and the residue was takendirectly into next step without further purification.

The crude mixture from previous Step was dissolved in anhydrous MeOH (70mL) and treated with K₂CO₃ (3.97 g, 28.8 mmol) at 45° C. for 1 hourbefore it was cooled down to 25° C. The mixture was diluted with EtOAc(200 mL) and the combined organic extracts were washed with aqueousNH₄Cl, brine, and dried over Na₂SO₄. The solvent was removed in vacuoand the residue was purified by flash column chromatography (0-40% EtOAcin hexanes) to give the desired product (2.2 g, 65% yield).

¹H NMR (CDCl₃, 300 MHz) δ: 1.23 (d, J=6.97 Hz, 4H), 1.64-1.80 (m, 8H),1.91-1.98 (m, 2H), 2.22-2.30 (m, 1H), 2.61-2.67 (m, 2H), 2.77 (s, 2H),3.14-3.23 (m, 1H), 3.42 (s, 2H), 6.79 (dd, J=11.21, 1.60 Hz, 1 H), 6.87(dd, J=7.82, 1.60 Hz, 1H), 7.15 (t, J=7.91 Hz, 1H). HRMS calcd forC₂₁H₂₈FO₃ (M+H⁺): 347.2017. Found: 347.2021.

Step 1: 2-(4-bromo-2-fluorophenyl)propan-2-ol

A solution of methyl 4-bromo-2-fluorobenzoate (8.0 g, 34.3 mmol) inanhydrous Et₂O (85 mL) was treated with MeMgBr (3.0 M in THF, 30 mL).The resulting solution was stirred at 25° C. for 3 hours before it wasquenched by the addition of H₂O (10 mL). The mixture was extracted withEtOAc (50 mL) three times and the combined organic extracts were washedwith aqueous NH₄Cl, brine, and dried over Na₂SO₄. The solvent wasremoved in vacuo and the residue was purified by flash columnchromatography (0-25% EtOAc in hexanes) to give the desired product (7.2g, 91% yield).

¹H NMR (CDCl₃, 300 MHz) δ: 1.62 (s, 6H), 7.19-7.22 (m, 1H), 7.27-7.29(m, 1H), 7.45-7.49 (m, 1H).

Step 2: 4-bromo-2-fluoro-1-isopropylbenzene

To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (7.6 g, 32.8mmol) dissolved in anhydrous CH₂Cl₂ (300 mL) at 25° C. was addedtriethylsilane (7.8 mL, 49.1 mmol), followed by trifluoroacetic acid (25mL, 328 mmol). The resulting solution was stirred at that temperaturefor 45 min. The solvent was removed in vacuo and the residue waspurified by flash column chromatography (0-10% EtOAc in hexanes) to givethe desired product (5.7 g, 80% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 1.23 (d, J=6.82 Hz, 3H), 3.15-3.22 (m, 1H),7.11 (t, J=8.08 Hz, 1H), 7.17 (dd, J=9.85, 1.77 Hz, 1H), 7.22 (d, J=8.34Hz, 1H).

Step 3:6-[2-cyclopentyl-4-(3-fluoro-4-isopropylphenyl)-2-hydroxybut-3-ynyl]-2,2-dimethyl-4H-1,3-dioxin-4-one

4-Bromo-2-fluoro-1-isopropylbenzene (5.0 g, 23.2 mmol),6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(5.56 g, 21.0 mmol) were dissolved in anhydrous DMF (30 mL). To thissolution, CuI (120 mg, 0.63 mmol), Pd(PPh₃)₂Cl₂ (0.59 g, 0.84 mmol), anddiisopropylamine (60 mL), were added sequentially. The mixture was thenheated at 90° C. for 20 min before it was cooled down to 25° C. Thereaction was diluted with EtOAc (150 mL) and washed with aqueous NH₄Cl,brine, and dried over Na₂SO₄. The solvent was removed in vacuo and theresidue was purified by flash column chromatography (040% EtOAc inhexanes) to give the desired product (7.5 g, 81% yield).

¹H NMR (CDCl₃, 300 MHz) δ: 1.22-1.28 (m, 8H), 1.69-1.74 (m, 10H),1.80-1.86 (m, 2H), 2.19-2.26 (m, 1H), 2.62-2.70 (m, 2H), 3.18-3.25 (m,1H), 5.46 (s, 1H), 7.00 (dd, J=10.61, 1.52 Hz, 1H), 7.09-7.11 (m, 1H),7.18 (t, J=7.71 Hz, 1H).

Example A(65)6-cyclopentyl-6-[2-(3-ethyl-4-fluorophenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(82), where4-bromo-2-ethyl-1-fluorobenzene was substituted in place of2-bromopyridine in Step 1 of that example. LCMS: 331-ve APCI. Anal.Calcd. For C₂₀H₂₅O₃F: C, 72.76; H, 7.58. Found: C, 72.87, H, 8.03.

Step 1: 4-bromo-2-ethyl-1-fluorobenzene

Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of(5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml,2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C.for 48 hrs. After which time the reaction mixture was cooled to roomtemperature and partitioned between ethyl acetate (100 ml) and water(100 ml). The organic layer was separated and dried over anhydroussodium sulfate, filtered and the solvent was removed in vacuo. The crudeoil was purified by column chromatography on silica gel eluting with80:20 hexanes:ethyl acetate, to afford the title compound as a yellowoil (0.4 g).

¹H NMR (CDCl₃): δ 1.19 (t, J=7.06 Hz, 3H), 3.45 (q, J=7.03 Hz, 2H), 7.10(m, 1H), 7.25 (m, 2H).

Example A(66):6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione.

The title compound was prepared analogously to Example A(86), where3-Bromo-ethylbenzene was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.81 (t, J=8.4 Hz, 1H), 1.30 to 1.80 (bm, 8H), 1.94(m, 2H), 2.26 (m, 1H), 2.59 (m, 4H), 2.72 (s, 2H), 3.39 (s, 2H), 6.95(m, 2H), 7.04 (d, J=5.2 Hz, 1H), 7.17 (m, 1H). ESIMS (M+H⁺): 315.19.

Example A(67){3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-aceticacid methyl ester

The title compound was prepared analogously to Example A(86), where(3-Bromo-phenyl)-acetic acid methyl ester was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.30 to 1.80 (bm, 8H), 1.90 (m, 2H), 2.23 (m, 1H),2.64 (m, 2H), 2.70 (s, 2H), 3.36 (s, 2H), 3.65 (s, 2H), 6.95 (m, 2H),7.00 (m, 2H), 7.09 (d, J=4.6 Hz, 1H) 7.22 (m, 1H). ESIMS (M+H⁺): 359.18.

Example A(68)6-Cyclopentyl-6-[2-(3,3-dimethyl-2-oxo-2,3-dihydro-benzofuran-5-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to example A(86), where5-Bromo-3,3-dimethyl-3H-benzofuran-2-one was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.55 (s, 6H), 1.59 to 1.89 (bm, 8H), 2.01 (m, 2H),2.33 (m, 1H), 2.74 (m, 2H), 2.83 (m, 2H), 3.48 (m, 2H), 7.05 (s, 1H),7.10 (s, 2H). ESIMS (M+H⁺): 371.18.

Step 1: 3,3-Dimethyl-3H-benzofuran-2-one

A solution of 3H-Benzofuran-2-one (4.02 g, 30 mmol) dissolved in THF (15mL) was added cautiously to a suspension of NaH (95% dry, 1.58 g, 66mmol) in DMF (60 mL) and THF (30 mL) under a nitrogen atmosphere, at 0°C. The mixture was stirred until gas evolution ceased, then Mel (5.6 mL,90 mmol) was added slowly to avoid boiling over. After Mel addition wascomplete the reaction further stirred 1 h at room temperature thenquenched by carefully pouring onto a mixture of HCl (1 N) and ice. Theresulting solution was extracted with ether, washed with brine, driedover MgSO4, and chromatographed on silica eluted with a gradient of5-50% ethyl acetate/hexanes, yielding 3.16 g (65% yield) of the product.

Step 2: 5-Bromo-3,3-dimethyl-3H-benzofuran-2-one

3,3-Dimethyl-3H-benzofuran-2-one (2.81 g, 17.3 mmol) was added to asolution of Bromine (1.51 mL, 29.5 mmoL) and Acetic acid (35 mL) at roomtemperature, then stirred overnight. The resulting mixture was strippedof solvent, then distilled under high vacuum. The product fraction (2.08g, 50%) was collected between 65° C. and 79° C.

Example A(69)1-{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-cyclopropanecarboxylicacid methyl ester

The title compound was prepared analogously to example A(86), where1-(3-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester wassubstituted in place of 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acidmethyl ester in Step 3 of that example.

¹H NMR (CDCl₃): δ 1.19 (s, 2H), 1.39 to 1.86 (bm, 10H), 1.98 (m, 2H),2.68 (m, 1H), 2.77 (s, 2H), 3.42 (s, 2H), 3.14 (s, 3H), 7.05 (d, J=2.7Hz, 1H), 7.14 (s, 1H), 7.24 (m, 2H). ESIMS (M+H⁺): 385.19.

Step 1: 1-(3-Bromo-phenyl)-cyclopropanecarboxylic Acid Methyl Ester

A solution of (3-Bromo-phenyl)-acetic acid methyl ester (4.54 g, 20mmol) dissolved in dry THF (10 mL) was added dropwise to suspension ofNaH (95% dry, 1.05 g, 44 mmol) in DMF (40 mL) and THF (10 mL), under anitrogen atmosphere, at 0° C. After 30 min, gas evolution ceased, and1,2-dibromoethane (3.79 mL, 44 mmol) was added dropwise over 20 min. Theresulting mixture was stirred for 1 h, then quenched with 1 N HCl,extracted with ether, washed with brine, dried over MgSO4, and strippedof solvent. The resulting oil was distilled under high vacuum. Theproduct was collected between 95° C. and 105° C. Yield 2 g, 39%.

Example A(70):{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-acetonitrile

The title compound was prepared analogously to example A(86), where(3-Bromo-phenyl)-acetonitrile was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.40 to 1.85 (bm, 8H), 1.97 (m, 2H), 2.28 (m, 1H),2.70 (t, J=7.1 Hz, 2H), 2.78 (s, 2H), 3.74 (s, 2H), 7.12 (m, 2H), 7.18(m, 1H), 7.30 (m, 1H). ESIMS (M+H⁺): 326.17.

Example A(71) 1H-Pyrazole-3-carboxylic acid(2-{3-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-amide

HATU (169.6 mg, 0.4464 mmol) was added to a solution of6-{2-[3-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dionetrifluoroacetic acid salt (175 mg, 0.372 mmol), Et₃N (207 μL, 1.488mmol), 1H-Pyrazole-3-carboxylic acid (50.0 mg, 0.4464 mmol), dissolvedin DMF (2 mL). The reaction was stirred overnight, then purifieddirectly by RPHPLC. Yield 55 mg, 33%.

¹H NMR (CDCl₃): δ 1.38 (s, 6H), 1.40 to 2.00 (bm, 10H), 2.36 (m, 1H),2.64 (m, 2H), 2.81 (m, 2H), 3.46 (m, 2H), 3.63 (m, 2H), 6.63 to 6.79(bm, 3H), 6.84 (s, 1H), 7.03 (s, 1H), 7.19 (s, 1H), 7.45 to 7.60 (bm,3H). ESIMS (M+Na⁺): 474.25.

Step 1: [2-(3-Bromo-phenyl)-2-methyl-propyl]-carbamic Acid Tert-ButylEster

2-(3-Bromo-phenyl)-2-methyl-propionitrile was added to a solution ofLithium aluminum hydride (1M in THF, 37.4 ml, 37.4 mmol), in dry THF (70mL), under a nitrogen atmosphere. The reaction was stirred for 5 h thenquenched by cautiously adding water (1.51 ml), followed by 15%NaOH/water (1.51 mL), followed by water (4.53 ml). A white precipitateformed which was removed by filtration. The resulting solution wastreated with di-tert butyl dicarbonate (1 M in THF, 37.4 mL, 37.4 mmol),and stirred for an additional 30 minutes. The reaction was stripped ofsolvent and purified by column chromatography (5% to 25% ethylacetate/hexanes). Yield 8.64 g, 87%.

Step 2:(2-{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-carbamicAcid Tert-Butyl Ester

The above compound was prepared analogously to example A(86), where[2-(3-Bromo-phenyl)-2-methyl-propyl]-carbamic acid tert-butyl ester(from Step 1 above) was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

Step 3:6-{2-[3-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dionetrifluoroacetic Acid Salt

(2-[3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl]-2-methyl-propyl)-carbamicacid tert-butyl ester (1.80 g, 3.94 mmol), was stirred with 30%TFA/CH₂Cl₂ (30 mL), for 2 h. The reaction was diluted with Toluene (30mL) and stripped of all solvents. The crude product was used withoutfurther purification. Yield 3.22 g.

Example A(72)N-(2-{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-3-furan-2-yl-propionamide

The title compound was prepared analogously to example A(71), where3-Furan-2-yl-propionic acid was substituted in place of1H-Pyrazole-3-carboxylic acid methyl ester in the final Step of thatexample. Yield 34 mg, 19%.

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.40 to 2.05 (bm, 9H), 2.08 to 3.13 (bm,12H), 3.44 (bs, 2H), 6.93 to 7.58 (bm, 8H). ESIMS (M+Na⁺): 502.27.

Example A(73) 4,5-Dimethyl-furan-2-carboxylic acid(2{3-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-amide

The title compound was prepared analogously to example A(71), where4,5-Dimethyl-furan-2-carboxylic acid was substituted in place of1H-Pyrazole-3-carboxylic acid methyl ester in the final Step of thatexample. Yield 23 mg, 13%.

¹H NMR (CDCl₃): δ 1.39 (bs, 6H), 1.43 to 1.84 (bm, 8H), 1.95 (s, 3H),2.10 (s, 3H), 2.17 (s, 2H), 2.33 (m, 1H), 2.65 (m, 4H), 3.44 (m, 2H),3.57 (m, 2H), 6.00 (bs, 1H), 6.83 (m, 1H), 7.19 (bm, 4H). ESIMS (M+Na⁺):502.27.

Example A(74) 5-Hydroxy-pyrazine-2-carboxylic acid(2{3-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-amide

The title compound was prepared analogously to example A(71), where5-Hydroxy-pyrazine-2-carboxylic acid was substituted in place of1H-Pyrazole-3-carboxylic acid methyl ester in the final Step of thatexample. Yield 6.4 mg, 4%.

¹H NMR (CDCl₃): δ 1.35 (bs, 6H), 1.49 to 1.89 (bm, 8H), 2.00 (m, 2H),2.23 (s, 1H), 2.66 (m, 2H), 2.78 (s, 2H), 3.45 (m, 2H), 3.59 (m, 2H),7.00 (m, 1H), 7.03 to 7.58 (bm, 5H), 7.99 (m, 1H), 8.11 (m, 1H). ESIMS(M+Na⁺): 502.24.

Example A(75)3-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl)-3-oxo-propionitrile

The title compound was prepared analogously to example A(86), where5-(4-Iodo-phenyl)-isoxazole was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example (Note that the isoxazole opens to the cyanomethyl ketoneduring the Sonogashira coupling Step). Yield 30 mg, 14%.

¹H NMR (CDCl₃): δ 1.18 to 1.70 (bm, 8H), 1.85 (m, 2H), 2.15 (m, 1H),2.67 (m, 4H), 3.31 (m, 2H), 3.94 (s, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.72(d, J=8.3 Hz, 2H). ESIMS (M+Na⁺): 376.16.

Example A(76)6-Cyclopentyl-6-[2-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to example A(86), where5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.971.4 to 1.88 (bm, 8H), 1.96 (m, 2H),2.30 (s, 1H), 2.63 (t, J=8.2 Hz, 2H), 2.79 (s, 2H), 3.46 (s, 2H), 4.24(s, 2H), 6.73 (d, J=6.5 Hz, 1H), 6.90 (m, 2H). ESIMS (M+H⁺): 357.20.

Step 1: 5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran-2-ol

To a solution of 5-Bromo-3,3-dimethyl-3H-benzofuran-2-one (1.199 g, 5.0mmol) (described in Step 2 of Example A(68), ), dissolved in anhydrousCH₂Cl₂ (20 ml), and cooled to −78° C., was added DIBAL (3.67 mL, 5.5mmol, 1.5M in Toluene). The reaction was stirred for 1 h at thistemperature then quenched with 1 N HCl until acidic. The resultingmixture was extracted with ether, which was washed with brine, driedwith MgSO4, concentrated and purified by silica gel chromatography(gradient elution 5-15% Ethylacetate/Hexanes). Yield 0.95 g, 79%.

Step 2: 5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran

A solution of 5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran-2-ol (813 mg,3.36 mmol), Triethylsilane (805 □L, 5.04 mmol), and 30% TFA/CH₂Cl₂ (15mL), were stirred at room temperature for 1 h. The solution was thendiluted with Toluene (15 mL), stripped of all solvents, andchromatographed on silica eluted with a gradient 5-25% Ethylacetate/Hexanes. Yield 549 mg, 72%.

Example A(77)6-Cyclopentyl-6-[2-(3-fluoro-4-thiazol-2-ylmethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to example A(86), where2-(4-Bromo-3-fluoro-benzyl)-thiazole (prepared below), was substitutedin place of 1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl esterin Step 3 of that example.

¹H NMR (CDCl₃): δ 1.40 to 1.85 (bm, 8H), 1.99 (m, 2H), 2.33 (m, 1H),2.75 (m, 2H), 2.86 (s, 2H), 3.50 (s, 2H), 4.44 (s, 2H), 6.94 (m, 2H),7.29 (m, 2H), 7.75 (d, J=3.5 Hz, 1H). ESIMS (M+H⁺): 402.15.

Step 1: (4-Bromo-3-fluoro-phenyl)-thiazol-2-yl-methanol

To a solution of Butyl lithium (9.6 mL, 24 mmol, 2.5 M in Hexane), inanhydrous Ether (80 ml), at −78° C., was added 2-Bromothiazole (2.0 mL,22 mmol). After stirring for 20 min at this temperature,4-Bromo-2-fluoro-benzaldehyde (20 mmol) was added, and stirring wascontinued an additional 30 min, then quenched with MeOH and Citric acid.The resulting mixture was extracted into ether, which was then washedwith NaHCO₃ (sat. aq.), brine, dried over MgSO₄, and purified by silicagel chromatography (gradient elution 15-50% Ethyl acetate/Hexanes).Yield 4.55 g, 79%.

Step 2: 2-(4-Bromo-3-fluoro-benzyl)-thiazole

A solution of (4-Bromo-3-fluoro-phenyl)-thiazol-2-yl-methanol (3.4 g,12.6 mmol), TFA (25 mL), and Triethylsilane (10 mL, 63 mmol), wererefluxed overnight. The reaction was then concentrated under vacuum, andpurified by silica gel chromatography (gradient elution 10-40%Ethylacetate/Hexanes). Yield 1.96 g, 61%.

Example A(78)6-Cyclopentyl-6-[2-(3-thiazol-2-ylmethyl-phenyl)-ethyl]-dihydro-pyran-2,4-Dione

The title compound was prepared analogously to example A(77), where3-Bromobenzaldehyde was substituted in place of4-Bromo-2-fluoro-benzaldehyde in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.40 to 1.85 (bm, 8H), 1.86 (m, 2H), 2.18 (m, 1H),2.58 (m, 2H), 2.67 (s, 2H), 3.33 (s, 2H), 4.27 (s, 2H), 6.96 to 7.20 (m,5H), 7.64 (d, J=3.3 Hz, 1H). ESIMS (M+H⁺): 384.16.

Example A(79)6-Cyclopentyl-6-{2-[4-(2-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-Dione

The title compound was prepared analogously to example A(86), where2-(4-Bromo-phenyl)-ethanol was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.40 to 1.82 (bm, 8H), 1.96 (m, 2H), 2.29 (m, 1H),2.66 (d, J=8.2 Hz, 2H), 2.76 (s, 2H), 2.84 (d, J=6.2 Hz, 1H), 3.41 (s,2H), 3.84 (d, J=6.6 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz,2H). ESIMS (M+H⁺): 331.18.

Example A(80)6-Cyclopentyl-6-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to example A(86), where2-(3-Bromo-phenyl)-ethanol was substituted in place of1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example.

¹H NMR (CDCl₃): δ 1.39 to 1.84 (bm, 8H), 1.99 (m, 2H), 2.30 (m, 1H),2.68 (d, J=8.6 Hz, 2H), 2.76 (s, 2H), 2.84 (d, J=6.6 Hz, 1H), 3.40 (s,2H), 3.86 (d, J=6.6 Hz, 1H), 7.02 (m, 2H), 7.08 (m, 1H), 7.23 (m, 1H).ESIMS (M+H⁺): 331.18.

Example A(81)2{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to Step 5 of Example A(86),substituting2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-methyl-propionitrile(1.23 g, 2.9 mmol) from Step 3 below in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 0.614 g, 56%.

¹H NMR (CDCl₃) δ: 1.24-1.66 (m, 14H), 1.75-1.80 (m, 2H), 2.10 (p, J=9.35Hz, 1H), 2.47-2.56 (m, 2H), 2.60 (d, J=5.56 Hz, 2H), 3.26 (d, J=3.28 Hz,2H), 6.71-6.79 (m, 2H), 7.23 (t, J=8.24 Hz, 1H). MS (ESI): 370 (M−H).

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to Example A(86), Step 2,substituting iodomethane (1.3 mL, 20.6 mmol) in place of1,2-dibromoethane. Yield: 2.25 g, 99%.

¹H NMR (CDCl₃) δ: 2.81 (s, 3H), 2.88 (s, 3H), 7.20-7.25 (m, 3H).

Step 2:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to Example A(86), Step 5,substituting 2-(4-bromo-2-fluoro-phenyl)-2-methyl-propionitrile (1.1 g,4.5 mmol) from Step 1 above in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 1.415 g,74%.

MS (ESI): 424 (M−H).

Step 3:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to example A(86), Step 6,substituting2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-methyl-propionitrile(1.25 g, 2.9 mmol) from Step 2 above in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 1.23 g, 99%.

MS (ESI): 428 (M−H).

Example A(82):6-Cyclopentyl-6-(2-pyridin-2-yl-ethyl)-dihydro-pyran-2,4-dione

Sodium hydride (60%) (0.24 g, 5.90 mmol) was magnetically stirred in dryTHF (12 mL) and cooled to 0° C. The mixture was then treated with Methylacetoacetate (0.64 mL, 5.90 mmol) dropwise over 15 min. The reaction wasallowed to stir for 30 min at 0° C. To the resulting clear solution wasadded nBuLi (1.6M in Hexanes) (3.68 mL, 5.90 mmol). The reaction wasthen allowed to stir for 30 min at 0° C. To the yellow solution wasadded the ketone from Step 1 below (0.4 g, 1.96 mmol) as a solution indry THF (6 mL). The result was stirred at 0° C. for 15 min and then atroom temperature for 90 min. The solution was next poured into 0.5N HCl(50 mL) and extracted with EtOAc (2×50 mL). The organics wereconcentrated and the residue dissolved in MeOH (12 mL) and treated withK₂CO₃ (0.6 g). The mixture was heated to 65° C. and maintained for 1 hr.The reaction was cooled and poured into 0.5N HCl (50 mL) and extractedwith EtOAc (2×50 mL). The organics were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (silicagel) eluting with CH₂Cl₂ through 1% MeOH in CH₂Cl₂ to yield the titlecompound as a white solid. (0.41 g, 73%).

¹H NMR (CDCl₃): δ 1.41-1.85 (brm, 8H), 1.95 (m, 2H), 2.29 (t, J=7.6 Hz,1H), 2.65 (t, J=8.6 Hz, 2H), 2.80 (s, 2H), 3.40 (s, 2H), 7.10 (d, J=6.6Hz, 1H), 7.24 (brs, 1H), 7.32 (m, 2H). ESIMS (MH+): 288.3.

Step 1: 1-Cyclopentyl-3-pyridin-2-yl-propan-1-one

To a magnetically stirring solution of 2-Bromopyridine (0.4 g, 2.61mmol) and 1-Cyclopentyl-2-propen-1-ol (1.5 eq, 0.49 g, 3.88 mmol) inanhydrous N-Methylpyrrolidinone (3.0 mL), under argon at roomtemperature, was added Sodium Bicarbonate (1.2 eq, 0.26 g, 3.10 mmol)followed by Dichlorobis (triphenylphosphine) palladium (II) (0.02 eq,36.7 mg, 0.05 mmol). The resulting mixture was heated to 140° C. in anoil bath and maintained for 4 hours. The dark reaction mixture wascooled to room temperature and poured into water (50 mL) and extractedwith EtOAc (2×25 mL). The organics were washed with water (50 mL) andbrine (50 mL) then dried over Na₂SO₄, filtered and concentrated. Thecrude residue was purified by flash chromatography (1% through 10% EtOAcin Hexanes) to yield the intermediate ketone as a yellow oil (0.43 g,81%).

¹HNMR(CDCl₃): δ ?1.45-1.87 (m, 8H), 2.70-2.95 (m, 5H), 7.10 (d, J=6.6Hz, 1H), 7.24(brs, 1H), 7.32 (m, 2H).

Example A(83)6-{2-[3-Chloro-4-(1-ethyl-propoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where4-Bromo-2-chloro-1-(1-ethyl-propoxy)-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.04 (t, J=7.5 Hz, 6H), 1.52-1.86 (brm, 12H), 1.92 (m,2H), 2.27 (m, 1H), 2.65 (t, J=7.9 Hz, 2H), 2.76 (s, 2H), 3.43 (s, 2H),4.48 (m, 1H), 6.81-6.92 (m, 3H). Anal. Calcd. For C₂₃H₃₁ClO₄: C, 67.88;H, 7.68. Found: C, 67.63; H, 7.43.

Example A(84)6-[2-(5-Acetyl-thiophen-2-yl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(82), where1-(5-Bromo-thiophen-2-yl)-ethanone was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.49-1.79 (brm, 8H), 2.05-2.25 (m, 2H), 2.27 (m, 1H),2.55 (s, 3H), 2.71 (d, J=15.8 Hz, 1H), 2.79 (d, J=15.8 Hz, 1H), 2.96 (m,2H), 3.45 (s, 2H), 6.83 (d, J=3.5 Hz, 1H), 7.52 (d, J=3.5 Hz, 1H). Anal.Calcd. For C₁₈H₂₂O₄S: C, 64.64; H, 6.63. Found: C, 64.34; H, 6.73.

Example A(85)4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-methyl-benzenesulfonamide

The title compound was prepared analogously to Example A(82), where4-Bromo-2-fluoro-N-methyl-benzenesulfonamide was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.50-1.82 (brm, 8H), 1.92 (m, 2H), 2.27 (m, 1H), 2.63(s, 3H), 2.79 (m, 4H), 3.38 (s, 2H), 7.02-7.41 (m, 2H), 7.70 (s, 1H).Anal. Calcd. For C₁₉H₂₄FNO₅S: C, 57.42; H, 6.09; N, 3.52. Found: C,57.60; H, 6.22; N, 3.25.

Example A(86)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

A solution of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(0.9 g, 2.1 mmol) from Step 6 below in NaOH (0.3 M in MeOH, 21 mL, 6.3mmol) was stirred at room temperature for 3 hours. The reaction was thenquenched with 100 mL saturated NH₄Cl and 5 mL 1 N HCl. To this solutionwas added 100 mL CH₂Cl₂ and the layers were separated. The aqueous layerwas extracted with 2×100 mL CH₂Cl₂ and the organic layers were combined.After drying the organic with MgSO₄, and filtering to remove the solids,the solvent was removed by rotary evaporation. The remaining oil waspurified by flash chromatography to yield the desired product (0.367 g,47%).

¹H NMR (CDCl₃) δ: 1.27-1.30 (m, 2H), 1.51-1.73 (m, 10H), 1.84-1.89 (m,2H), 2.19 (p, J=8.08 Hz, 1H), 2.58-2.71 (m, 4H), 3.36 (d, J=4.04 Hz,2H), 6.81-6.86 (m, 2H), 7.16-7.18 (m, 1H). MS (ESI): 368 (M−H).

Step 1: (4-Bromo-2-fluoro-phenyl)-acetonitrile

To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (8.15 g, 30.4mmol) dissolved in DMF (16 mL) were added sodium cyanide (2.24 g, 45.6mmol) and water (2 mL). The reaction was stirred for one hour at 70° C.To the reaction was added 130 mL water; 120 mL saturated NaHCO₃, and 100mL EtOAc. The layers were separated, and the aqueous layer was extractedwith 3×100 mL EtOAc. The combined organics were washed with 100 mLwater, and then dried over Na₂SO₄. After filtering off the solids, themother liquor was concentrated to the desired product by rotaryevaporation (6.5 g, 99% yield).

MS (APCI): 240 (M+H), 242 (M+2+H).

Step 2: 1-(4-Bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile

To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g,20.6 mmol) in DMF (20 mL) cooled to 0° C. was added a solution of(4-bromo-2-fluoro-phenyl)-acetonitrile (2.0 g, 9.35 mmol) from Step 1above dissolved in THF (10 mL). The reaction was stirred till gasevolution ceased, and then 1,2-dibromoethane (1.8 mL, 20.6 mmol) wasadded slowly. The reaction was stirred for 30 minutes, and then dilutedwith 100 mL EtOAc. The solids were removed by filtration, and theorganic layer was washed with 100 mL water. The organic layer was driedover MgSO₄, and then filtered. The mother liquor was concentrated byrotary evaporation, and the product was distilled under high vacuum (0.3torr, 45° C.). Yield: 0.98 g, 44%.

¹H NMR (CDCl₃) δ: 1.15 (dd, J1=5.31 Hz, J2=2.27 Hz, 2H), 1.48 (dd,J1=5.05 Hz, J2=2.53 Hz, 2H), 6.97-7.12 (m, 3H).

Step 3: 1-Cyclopentyl-3-trimethylsilanyl-propynone

The title compound was prepared as described in the following reference:Journal of Organic Chemistry 1984, 106, 4786-4800.

¹H NMR (CDCl₃): δ 0.24 (s, 9H), 1.63 (m, 4H), 1.90 (m, 4H), 2.92(pentet, 1H, J=8.2 Hz).

Step 4:6-(2-Cyclopentyl-2-hydroxy-4-trimethylsilanyl-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one

A solution of diisopropylamine (3.85 mL, 27.5 mmol) dissolved in THF(100 mL; dry), was cooled to −78° C., where BuLi (11 mL, 27.5 mmol; 2.5M in hexanes) was added dropwise over 10 minutes. After stirring at thistemperature for 5 minutes the mixture was warmed to room temperature for5 minutes, then cooled back to −78° C., where commercially available2,2,6-trimethyl-[1,3]dioxin-4-one (3.60 mL, 27.5 mmol) was addeddropwise over 5 minutes, then stirred an additional 30 minutes at −78°C. To this solution was added 1-Cyclopentyl-3-trimethylsilanyl-propynone(4.85 g, 25 mmol; prepared as described in Step 3 above over 5 minutes.The resulting mixture was stirred at −78° C. for 1 hr, then slowlywarmed to −30° C. and quenched with 0.5 N citric acid. The mixture wasdiluted with ether, extracted with 1 N NaHCO₃, brine, and then driedwith MgSO₄. This material (9.38 g), which contained a unreacted2,2,6-trimethyl-[1,3]dioxin-4-one, was used without furtherpurification.

¹H NMR (CDCl₃) δ: 0.15 (s, 9H), 1.60 (m, 4H), 1.72 (s, 3H), 1.75 (s,3H), 2.01 (s, 1H), 2.14 (pentet, 1H), 2.47 (s, 1H), 2.55 (s, 2H), 5.40(s, 1H). ESIMS (M+Na⁺): 359.1.

Step 5:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

The desired product was prepared analogously to example F(7), Step 5,substituting 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile (0.96g, 4.0 mmol), from Step 2 above in place of 3-iodophenol, and6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one(1.06 g, 4.0 mmol; from Step 4 above) in place of6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield:1.241 g, 73%.

MS (ESI): 422 (M−H).

Step 6:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

To a solution of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(1.0 g, 2.4 mmol) from Step 5 above dissolved in EtOH (20 mL) was addedPd(OH)₂/C (20% wt dry basis, 100 mg) and the reaction was stirred undera hydrogen atmosphere for 6 hours. The palladium catalyst was removed byfiltration, and the solvent removed by rotary evaporation. The resultingoil was used without further purification (1.02 g, 99% yield).

MS (ESI): 426 (M−H).

Example A(87)N-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenyl}-N-methylmethanesulfonamide

The title compound was prepared analogously to Example A(64) whereN-(4-bromo-2-ethylphenyl)-N-methylmethanesulfonamide was substituted inplace of 4-bromo-2-fluoro-1-isopropylbenzene in step 2 of that example.

¹H NMR (CDCl₃): δ 1.12 (t, J−7.54 Hz, 3H), 1.4-2.2 (brm, 11H), 2.60-2.80(bmm, 6H), 2.94 s, 3), 3.02(s, 3H), 6.56 (d, J=4.90 Hz, 1H), 7.00, (d,J=4.90 Hz, 1H), 7.07 (s, 1H). Anal. Calcd. For C₂₂H₃₁NO₅S: C, 62.68; H,7.41; N, 3.32. Found: C, 62.49; H, 6.98; N, 3.20.

Step 1: N-(4-bromo-2-ethylphenyl)methanesulfonamide

Methane sulfonyl chloride (1.93 ml, 0.025M) was added to a solution of4-bromo-2-ethylaniline (5.0 g, 0.025M) and pyridine (2.02 ml, 0.025M) indichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1hr, after which time it was partitioned between dichloromethane (100 ml)and 1N hydrochloric acid (100 ml). The organics were separated and driedover magnesium sulfate, filtered and concentrated in vacuuo to affordthe title compound as a clear oil (4.77 g).

¹HNMR(CDCl₃): δ 1.12 (t, J=8.60 Hz, 3H), 2.91 (q, 2H), 3.06 (s, 3H),6.81 (d, J=7.54 Hz, 1H), 7.05 (d, J=7.54 Hz, 1H), 7.26 (s, 1H).

Step 2: N-(4-bromo-2-ethylphenyl)-N-methylmethanesulfonamide

Methyl iodide (1.6 g, 0.0256M) was added to a mixture ofN-(4-bromo-2-ethylphenyl)methanesulfonamide (4.77 g, 0.0171M) andpotassium carbonate (3.5 g, 0.0256M) in dimethylformamide (50 ml) atroom temperature under an atmosphere of nitrogen. The reaction mixturewas stirred for a further 24 hrs after which time it was partitionedbetween diethylether (100 ml) and water (100 ml). The aqueous wasextracted further with diethyl ether (2×100 ml). The combined organicswere dried over magnesium sulfate, filtered and the solvent concentratedin vacuuo to afford the title compound as a brown oil (3.6 g).

¹H NMR (CDCl₃): δ 1.12 (t, J=8.60 Hz, 3H), 2.94 (m, 5H), 3.02 (s, 3H),6.71 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.28 (s, 1H).

Example A(88)N-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]phenyl}-N-methylmethanesulfonamide

The title compound was prepared analogously to Example A(64) whereN-(4-bromophenyl)-N-methylmethanesulfonamide was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in step 2 of that example.

¹H NMR (CDCl₃): δ 1.4-2.24 (brm, 11H), 2.60-2.89 (brm, 4H), 2.94 (s,3H), 3.04 (m, 5H), 6.96 (dd, J=4, 96 Hz, 2H), 7.23 (dd, J=4.96 Hz, 2H).Anal. Calcd. For C₂₀H₂₇NO₅S: C, 61.04; H, 6.91; N, 3.56. Found: C,61.35; H, 6.94; N, 3.20.

Step 1: N-(4-bromophenyl)methanesulfonamide

Methane sulfonyl chloride (2.4 ml, 0.031 M) was added to a solution of4-bromo-aniline (5.28 g, 0.031 M) and pyridine (2.5 ml, 0.031 M) indichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1hr, after which time it was partitioned between dichloromethane (100 ml)and 1N hydrochloric acid (100 ml). The organics were separated and driedover magnesium sulfate, filtered and concentrated in vacuuo to affordthe title compound as a white solid (6.37 g).

¹H NMR (CDCl₃): 2.97 (s, 3H), 6.81 (d, J=2.56 Hz, 2H), 7.25 (d, J=2.56Hz, 2H),).

Step 2: N-(4-bromophenyl)-N-methylmethanesulfonamide

Methyl iodide (2.38 g, 0.0382M) was added to a mixture ofN-(4-bromophenyl)methanesulfonamide (6.37 g, 0.0255M) and potassiumcarbonate (5.21 g, 0.0382M) in dimethylformamide (50 ml) at roomtemperature under an atmosphere of nitrogen. The reaction mixture wasstirred for a further 24 hrs after which time it was partitioned betweendiethylether (100 ml) and water (100 ml). The aqueous was extractedfurther with diethyl ether (2×100 ml). The combined organics were driedover magnesium sulfate, filtered and the solvent concentrated in vacuuoto afford the title compound as a white solid (5.6 g).

¹H NMR (CDCl₃): 2.94 (s, 3H), 3.04 (s, 3H), 6.89 (d, J=2.56 Hz, 2H),7.30 (d, J=2.56 Hz, 2H),).

Example A(89)6-cyclopentyl-6-[2-(3-cyclopentyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(22): where4-bromo-2-cyclopentylphenol, from step 1, was used in place of4-Bromo-2-ethyl-phenol in step 2 of that example.

¹H NMR (CDCl₃): δ 1.43-1.85 (br m, 16H), 1.87-2.21, (m, 3H), 2.70-3.18(brm, 7H), 4.95 (s, 1H), 6.60 (d, J=8.1 Hz 1H)), 6.84 (d, J=8.1 Hz, 1H),7.12 (s, 1H). LCMS=369-ve APCI.

Step 1. 4-bromo-2-cyclopentylphenol

2-cyclopentyl phenol (3.0 g, 0.0185 mol) was dissolved in CHCl₃ (100 mL)and magnetically stirred at room temperature. To this solution was addeda solution of Tetrabutyl ammonium tribromide (8.92 g, 0.0185 mol) inCHCl₃ (100 mL). The resulting yellow solution was allowed to stir atroom temperature for 1 hour. The reaction was quenched with a 5%solution of sodium thiosulfate (200 mL). The biphasic mixture wasstirred for 15 min. The organics were separated and concentrated. Theresidue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL)and brine (1×100 mL). The organics were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (silicagel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (3.70g).

¹H NMR (CDCl₃): δ 1.39-1.73 (brm, 8H), 2.83 (m, 1H), 4.81 (s, 1H), 6.68(d, J=7.10 Hz 1H), 7.19 (d, J=7.10 Hz, 1H), 7.26(s, 1H).

Example A(90)6-cyclopentyl-6-[2-(4-hydroxy-3-propylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(22): where4-bromo-2-propylphenol, from step 1, was used in place of4-Bromo-2-ethyl-phenol in step 2 of that example.

¹H NMR(CDCl₃): δ 1.00(t, J=8.1 Hz3H,), 1.33-1.85(brm, 8H), 1.87-2.01(m,2H), 2.22(m, 3H), 2.30 (m, 2H), 2.60-3.10(brm, 6H), 5.78(s, 1H), 6.70(d,J=2.07 Hz1H)), 6.80(s, 1H), 6.85(d, J=2.07 Hz, 1H). LCMS=343-ve APCI.

Step 1. 4-bromo-2-propylphenol

2-propylphenol (3.0 g, 0.022 mol) was dissolved in CHCl₃ (100 mL) andmagnetically stirred at room temperature. To this solution was added asolution of Tetrabutyl ammonium tribromide (10.68 g, 0.022 mol) in CHCl₃(100 mL). The resulting yellow solution was allowed to stir at roomtemperature for 1 hour. The reaction was quenched with a 5% solution ofsodium thiosulfate (200 mL). The biphasic mixture was stirred for 15min. The organics were separated and concentrated. The residue wasdissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine(1×100 mL). The organics were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (silicagel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (4.54g).

¹HNMR(CDCl₃): δ 1.00 (t, J=8.10 Hz, 3H), 1.52 (m, 2H), 2.50 (t, J=4.56Hz, 2H), 4.95 (s, 1H), 6.72 (d, J=2.07 Hz 1H)), 6.80 (s, 1H), 6.85 (d,J=2.07 Hz, 1H).

Example A(91)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A(86) step 5,substituting2-(4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile(0.84 g, 1.8 mmol) from step 3 below in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 0.393 g, 54%.

¹H NMR (CDCl₃) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62-1.90 (br, 8H), 2.03-2.17(br, 4H), 2.20-2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75-2.82 (m,2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd,J1=13.01 Hz, J2=1.64 Hz, 1H), 7.04 (dd, J1=7.83 Hz, J2=1.77 Hz, 1H),7.57 (t, J=8.21 Hz, 1H).

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A(86) step 2,substituting bromoethane (1.94 mL, 20.6 mmol) in place of1,2-dibromoethane. Yield: 2.1 g, 84%.

MS (APCI) 270 (M+H), 272 (M+2+H).

Step 2:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A(86) step 5,substituting 2-(4-Bromo-2-fluoro-phenyl)-2-ethyl-butyronitrile (1.01 g,4.0 mmol) from step 1 above in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 0.953 g,53%.

MS (ESI): 436 (M−H).

Step 3:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-x-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to example A(86) step 6,substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile(0.900 g, 2.0 mmol) from step 2 above in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 0.841 g, 92%.

MS (ESI): 456 (M−H).

Example A(92)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

The desired product was prepared analogously to Example A(86) step 5substituting1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile(1.00 g, 2.2 mmol) from step 3 below in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 0.477 g, 57%.

¹H NMR (CDCl₃) δ: 1.79-2.05 (br, 8H), 2.14-2.19 (m, 2H), 2.21-2.29 (m,1H), 2.49 (p, J=9.35 Hz, 1H), 2.65-2.76 (m, 1H), 2.83-2.95 (m, 4H), 3.00(d, J=5.05 Hz, 2H), 3.02-3.10 (m, 2H), 3.66 (d, J=3.28 Hz, 2H), 7.12(dd, J1=11.24 Hz, J2=1.64 Hz, 1H), 7.17 (dd, J1=7.96 Hz, J2=1.64 Hz,1H), 7.38 (t, J=7.96 Hz, 1H).

Step 1: 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile

To a slurry of NaH (1.64 g, 60% suspension in mineral oil, 41.1 mmol) inDMSO (19 mL) stirred at room temperature, was added a solution of1,3-dibromopropane (2.1 mL, 20.6 mmol) and(4-Bromo-2-fluoro-phenyl)-acetonitrile (4.0 g, 18.7 mmol) in diethylether (10 mL) slowly keeping the temprature of the reaction between 25degrees Celsius and 35 degrees Celsius. Stir for two hours after theaddition is complete, and pour into saturated ammonium chloride (150mL). Add 100 ml of CH₂Cl₂ and separate the layers. Extract the aqueousphase with 2×50 mL CH₂Cl₂ and combine the organics. After drying theorganic liquid over MgSO₄, the solids were removed by filtration, andthe liquid was concentrated to an oil. The oil was purified by flashchromatography to yield the desired product. Yield: 1.43 g, 30%.

MS (APCI) 254 (M+H), 256 (M+2+H).

Step 2:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

The desired product was prepared analogously to Example A(86) step 5,substituting 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile (1.06g, 4.0 mmol) from step 1 above in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 1.226 g,70%.

MS (ESI): 436 (M−H).

Step 3:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

The desired product was prepared analogously to Example A(86) step 6,substituting1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile(1.200 g, 2.7 mmol) from step 2 above in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.Yield: 1.00 g, 84%.

MS (ESI): 440 (M−H).

Example A(93)6-Cyclopentyl-6-[2-(4-hydroxy-3-isopropyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(22) whereAcetic acid4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-phenylester (Example A(94)) was substituted in place of acetic acid4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenylester.

¹H NMR (CDCl₃): δ 1.24 (d, 6H, J=6.8 Hz), 1.47-1.81 (br m, 8H),1.87-2.01 (m, 2H), 2.27 (m, 1H), 2.60 (m, 2H), 2.77 (s, 3H), 3.18 (m,1H), 3.42 (s, 1H), 4.80 (s, 1H), 6.67 (d, 1H, J=8.1 Hz), 6.83 (dd, 1H,J=8.1, 2.3 Hz), 6.94 (d, 1H, J=2.3 Hz). Anal. Calcd. ForC₂₁H₂₈O₄.0.3H₂O: C, 72.09; H, 8.24. Found: C, 72.12; H, 8.23.

Example A(94) Acetic acid4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-phenylester

The title compound was prepared analogously to Example A(64) whereAcetic acid 4-bromo-2-isopropyl-phenyl ester (from step 2) wassubstituted in place of 4-bromo-2-fluoro-1-isopropylbenzene.

Step 1: 4-Bromo-2-isopropyl-phenol

The title compound was prepared as described in Step 1 of Example A(2)where 2-isopropyl-phenol was substituted in place of 2-ethyl-phenol.

¹H NMR (CDCl₃): δ 1.23 (d, 6H, J=7.1 Hz), 3.17 (m, 1H), 4.87 (br s, 1H),6.63 (d, 1H, J=8.5 Hz), 7.16 (dd, 1H, J=8.5, 2.3 Hz), 7.28 (d, 1H, J=2.5Hz).

Step 2: Acetic Acid 4-bromo-2-isopropyl-phenyl Ester

The title compound was prepared as described in Step 2 of Example A(22)where 4-Bromo-2-isopropyl-phenol from step 1, was substituted in placeof 4-Bromo-2-ethyl-phenol.

¹H NMR (CDCl₃): δ 1.20 (d, 6H, J=7.1 Hz), 2.32 (s, 3H), 2.98 (m, 1H),6.88 (d, 1H, J=8.6 Hz), 7.31 (dd, 1H, J=8.6, 2.3 Hz), 7.41 (d, 1H, J=2.5Hz).

Example A(95)6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(13) where3-(3-Chloro-4-hydroxy-phenyl)-1-cyclopentyl-propan-1-one was substitutedin place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹H NMR (CDCl₃): δ 1.44-1.80 (br m, 8H), 1.93 (m, 2H), 2.26 (m, 1H), 2.60(m, 2H), 2.73 (d, 1H, J=15.9 Hz), 2.78 (d, 1H, J=15.9 Hz), 3.43 (s, 2H),5.44 (s, 1H), 6.94 (m, 2H), 7.10 (s, 1H). Anal. Calcd. For C₁₈H₂₁O₄Cl:C, 64.19; H, 6.28. Found: C, 64.33; H, 6.39.

Example A(96)6-Cyclopentyl-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(13) where1-Cyclopentyl-3-(3-ethyl-4-methoxy-phenyl)-propan-1-one (from step 2)was substituted in place of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

¹HNMR(CDCl₃): δ 1.17 (t, 3H, J=7.3 Hz), 1.44-1.80 (brm, 8H), 1.95 (m,2H), 2.28 (m, 1H), 2.57-2.63 (m, 4H), 2.77 (s, 2H), 3.42 (s, 2H), 3.80(s, 3H), 6.75 (d, 1H, J=8.1 Hz), 6.91-6.94 (m, 2H). Anal. Calcd. ForC₂₁H₂₈O₄.0.2H₂O: C, 72.47; H, 8.23. Found: C, 72.52; H, 8.25.

Step 1: 4-Bromo-2-ethyl-1-methoxy-benzene

¹H NMR (CDCl₃): δ 1.17 (t, 3H, J=7.4 Hz), 2.59 (q, 2H, J=7.4 Hz), 3.80(s, 3H), 6.70 (d, 1H, J=8.8 Hz), 7.26 (m, 2H).

Potassium carbonate (3.9 g, 28.3 mmol) and methyl iodide (0.59 mL, 9.43mmol) were added to a solution of 4-Bromo-2-ethyl-phenol (1.9 g, 9.43mmol, from step 1 of Example A(22)) dissolved in DMF (10 mL). Themixture was stirred for 16 h under N₂ and then partitioned between 1 NHCl and EtOAc. The organic layer was washed with saturated NaHCO₃,brine, dried over Na₂SO₄ and concentrated to a yellow oil. The oil waspurifed by silica gel chromatography to give the title compound as aclear oil (1.37 g, 68%).

Step 2: 1-Cyclopentyl-3-(3-ethyl-4-methoxy-phenyl)-propan-1-one

A mixture of bromide (1.3 g, 6.02 mmol, from step 1),1-Cyclopentyl-2-propen-1-ol (1.14 g, 9.07 mmol), dichlorobis(triphenylphosphine) palladium (II) (85 mg, 0.12 mmol), sodiumbicarbonate (0.61 g, 7.25 mmol) in N-methylpyrrolidinone (12 mL) washeated to 140° C. under N₂ for 5 h. The reaction mixture was partitionedbetween 1 N HCl and EtOAc. The organic layer was washed with saturatedNaHCO₃, brine, dried over Na₂SO₄ and concentrated to a brown oil. Theoil was purifed by silica gel chromatography to give the title compoundas a yellow oil (0.74 g, 47%).

¹H NMR (CDCl₃): δ ?1.17 (t, 3H, J=7.6 Hz), 1.54-1.80 (m, 9H), 1.17 (q,2H, J=7.6 Hz), 2.73 (m, 2H), 2.84 (m, 2H), 3.80 (s, 3H), 6.75 (d, 1H,J=8.0 Hz), 6.97 (m, 2H).

Example A(97)2-[4-(2-{2-cyclopentyl-5-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

A solution of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile(300 mg, 0.81 mmol) in anhydrous MeOH (8.0 mL) was treated with2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde (167 mg, 1.21 mmol),followed by borane-dimethylamine complex (62 mg, 1.05 mmol) at roomtemperature. The reaction was stirred for 12 hours before it wasquenched by the addition of 1 N HCl. The mixture was extracted with 10%MeOH in CH₂Cl₂ (3×10 mL) and the combined organic layers were washedwith brine, dried over Na₂SO₄. The solvent was removed and the residuewas purified by HPLC to give product as a white powder (150 mg, 38%yield). ¹H NMR (300 MHz, DMSO-d₆) δ: 1.15-1.20 (m, 3H), 1.30-1.65 (m,8H), 1.71 (s, 6H), 1.85-1.93 (m, 2H), 2.10 (s, 3H), 2.25-2.40 (m, 2H),2.56-2.68 (m, 4H), 3.32-3.44 (m, 2H), 7.02-7.13 (m, 2H), 7.35 (t, J=8.38Hz, 1H). Anal. Calcd. For C₂₉H₃₆FN₃O₃.0.1H₂O: C, 70.30; H, 7.37; N,8.48. Found: C, 70.09; H, 7.37; N, 8.47.

Step 4: Preparation of Compound2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl)-2-methylpropanenitrile

To a solution of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile(4.25 g, 10.0 mmol) in MeOH (100 mL) was added Pd(OH)₂ (1.0 g, 20 wt %).The mixture was stirred under H₂ for 12 hours before it was filteredthrough a pad of celite. The solvent was removed and the residue wastaken directly into next step without further purification. The crudemixture was dissolved in anhydrous MeOH (100 mL) and treated with K₂CO₃(2.8 g, 10 mmol). The reaction was heated at 45° C. for 40 min before itwas cooled down to room temperature. The crude mixture was diluted withaqueous NH₄Cl and extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄. The solvent wasremoved and the mixture was purified by flash column chromatography(EtOAc in hexanes, 10-40% gradient) to give the desired product (1.4 g,35% for two steps). ¹H NMR (CDCl₃) δ: 1.60-1.73(m, 6H), 1.92-1.98 (m,2H), 2.22-2.30 (m, 1H), 2.65-2.71 (m, 2H), 2.75-2.80 (m, 2H), 6.88-6.96(m, 2H), 7.37-7.43 (m, 1H).

Step 3: Preparation of Compound2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile

To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (3.0g, 12.4 mmol) in diisopropylamine (32 mL) and DMF (16 mL) was added6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(3.2 g, 12.4 mmol), PdCl₂(PPh₃)₂ (350 mg, 4 mol %), CuI (71 mg, 3 mol%). The mixture was heated to 90° C. for 30 min before it was cooleddown to room temperature. The reaction was diluted with aqueous NH₄Cl,extracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine, dried with Na₂SO₄ and evaporated to dryness. Themixture was purified by flash column chromatography (10-50% EtOAc inhexanes) to give the product (4.2 g, 79% yield). ¹H NMR (300 MHz, CDCl₃)δ: 1.65-1.76 (m, 14H), 1.79 (s, 6H), 1.82-1.85 (m, 1H), 2.24 (s, 1H),2.59 (s, 1H), 2.67 (m, 2H), 5.46 (m, 1H), 7.11 (dd, J=12.15, 1.60 Hz,1H), 7.18 (dd, J=8.10, 1.70 Hz, 1H), 7.45 (t, J=8.10 Hz, 1H).

Step 2: Preparation of Compound2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile

To a solution of Mel (3.2 mL, 49.3 mmol) in anhydrous DMF (82 mL) at 0°C. was added NaH (60%, 2.0 g), followed by(4-bromo-2-fluorophenyl)acetonitrile (3.5 g, 16.4 mmol). The mixture wasslowly warmed up to room temperature and stirred for 3 hours. Thereaction was quenched by the addition of saturated NH₄Cl and extractedwith EtOAc (3×150 mL). The combined organic extracts were washed withbrine, dried with Na₂SO₄ and evaporated to dryness. The mixture waspurified by flash column chromatography (0-20% EtOAc in hexanes) to givethe product (3.0 g, 77% yield). ¹H NMR (300 MHz, CDCl₃) δ: 1.78 (s, 6H),7.26-7.42 (m, 3H).

Step 1: Preparation of Compound (4-bromo-2-fluorophenyl)acetonitrile

To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.0 g, 18.7mmol) in DMF (80 mL) and H₂O (8 mL) was added KCN (1.21 g, 18.7 mmol).The mixture was heated to 40° C. for 3 hours before it was cooled downto room temperature. The reaction was diluted with H₂O (40 mL) andextracted with Et₂O (3×100 mL). The combined organic layers were washedwith brine and dried over Na₂SO₄. The solvent was removed and theresidue was purified by flash column chromatography (0-15% EtOAc inhexanes) to give the product (3.5 g, 87% yield). ¹H NMR (300 MHz, CDCl₃)δ: 3.72 (s, 2H), 7.26-7.35 (m, 3H).

Example A(98)2-[4-(2-{5-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), where5-chloro-1-methyl-1H-benzimidazole-2-carbaldehyde was substituted inplace of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300 MHz,DMSO-d₆) δ: 1.14-1.49 (m, 8H), 1.52 (s, 6H), 1.87-2.07 (m, 2H),2.15-2.25 (m, 2H), 2.38-2.46 (m, 2H), 2.56-2.62 (m, 1H), 3.49-3.65 (m,2H), 3.58 (s, 3H), 6.86 (dd, J=8.01, 1.22 Hz, 1H), 6.98 (m, 2H), 7.14(m, 2H), 7.30 (d, J=8.67 Hz, 1H). HRMS: calcd for C₃₁H₃₄ClFN₃O₃ (M+H⁺)550.2267, found 550.2273.

Step 3: 5-chloro-1-methyl-1H-benzimidazole-2-carbaldehyde

A solution of (5-chloro-1-methyl-1H-benzimidazol-2-yl)methanol (1.5 g,7.7 mmol) dissolved in CH₂Cl₂ at room temperature was treated withDess-Martin periodinane (4.9 g, 11.5 mmol). The reaction was stirred for15 hours before the solvent was removed. The residue was purified byflash column chromatography (0-3% MeOH in CH₂Cl₂) to give the product(1.0 g, 66% yield). ¹H NMR (300 MHz, CDCl₃) δ: 4.16 (s, 3H), 7.40-7.47(m, 2H), 7.90-7.93 (m, 1H), 10.11 (s, 1H).

Step 2: (5-chloro-1-methyl-1H-benzimidazol-2-yl)methanol

4-chloro-N¹-methylbenzene-1,2-diamine (15.0 g, 96 mmol) and glycolicacid (8.1 g, 106 mmol) were mixed together in a sealed tube. The mixturewas heated at 150° C. for 5 hours before it was cooled down to roomtemperature. The residue was purified by flash column chromatography(0-5% MeOH in CH₂Cl₂) to give the product (8.5 g, 45% yield). ¹H NMR(300 MHz, CDCl₃) δ: 3.80 (s, 3H), 4.86 (s, 2H), 7.13-7.22 (m, 2H),7.62-7.64 (m, 1H).

Step 1: 4-chloro-N′-methylbenzene-1,2-diamine

A solution of 1,4-dichloro-2-nitrobenzene (5 g, 26 mmol) dissolved in33% MeNH₂ in EtOH (20 mL) was heated to 80° C. for 15 hours. Thereaction was cooled to room temperature and the solvent was removed. Thecrude product was taken directly into next step without furtherpurification.

The mixture dissolved in EtOH (250 mL) was treated with Zn dust (15 g),followed by dropwise addition of aqueous HCl (6 N, 40 mL). The reactionwas stirred at room temperature for 3 hours. The solution was made basicby slow addition of saturated NaOH. The aqueous was extracted withCH₂Cl₂ (3×100 mL). The combined organic layers were washed with brineand dried over Na₂SO₄. The solvent was removed to afford product (1.7 g,42% yield for two steps).

¹H NMR (300 MHz, CDCl₃) δ: 2.84 (s, 3H), 6.54 (d, J=6.0 Hz, 1H), 6.70(d, J=3.0 Hz, 1H), 6.79 (dd, J=3.0, 6.0 Hz, 1H).

Example A(99)2-[4-(2¶-cyclopentyl-4-hydroxy-6-oxo-5-[(2-oxo-1,2-dihydropyridin-4-yl)methyl]-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), where2-oxo-1,2-dihydropyridine-4-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300 MHz, DMSO-d₆):1.25-1.78 (m, 8H), 1.71 (s, 6H), 1.87-1.93 (m, 2H), 2.56-2.64 (m, 2H),2.71-2.76 (m, 1H), 3.25-2.26 (m, 4H), 7.00-7.03 (m, 1H), 7.09-7.20 (m,3H), 7.23-7.28 (m, 1H), 7.32-7.38 (m, 1H). HRMS: calcd for C₂₈H₃₂FN₂O₄(M+H⁺) 479.2341, found 479.2331.

Step 1: 2-oxo-1,2-dihydropyridine-4-carbaldehyde

The title compound was prepared as described in the following reference:J. Am. Chem. Soc., 1997, 3619-3620.

Example A(100)2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(3-methoxybenzyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), where3-methoxybenzaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.24-1.66 (m, 8H), 1.71 (s, 6H), 1.83-1.93(m, 2H), 2.27-2.36 (m, 2H), 2.54-2.59 (m, 2H), 2.73-2.79 (m, 1H),3.42-3.56 (m, 2H), 3.65 (s, 3H), 6.69-6.77 (m, 3H), 6.93-7.19 (m, 3H),7.30-7.36 (m, 1H). Anal. Calcd. For C₃₀H₃₄FNO₄.0.3H₂O: C, 72.50; H,7.02; N, 2.82. Found: C, 72.13; H, 6.97; N, 2.88.

Step 1: 3-methoxybenzaldehyde

A solution of 3-hydroxybenzaldehyde (1.22 g, 10 mmol) in anhydrousacetone (50 mL) was treated with K₂CO₃ (2.76 g, 20 mmol) and Mel (0.9mL, 15 mmol) at room temperature for 12 hours. The mixture was pouredinto water and extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine and dried over Na₂SO₄. The solvent wasremoved and the product was purified by flash column chromatography(0-15% EtOAc in hexanes, 1.2 g, 88% yield). ¹H NMR (300 MHz, CDCl₃) δ:3.88 (s, 3H), 7.17-7.21 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.47 (m, 2H),9.99 (s, 1H).

Example A(101)2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[3-(methylsulfonyl)benzyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), where3-(methylsulfonyl)benzaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300 MHz, DMSO-d₆)δ: 1.23-1.64 (m, 8H), 1.70 (s, 6H), 1.84-1.91 (m, 2H), 2.26-2.34 (m,1H), 2.54-2.59 (m, 2H), 2.68-2.74 (m, 1H), 3.10 (s, 3H), 3.17 (s, 1H),3.55-3.66 (m, 2H), 6.92-6.95 (m, 1H), 7.04-7.09 (m, 1H), 7.30-7.35 (m,1H), 7.46-7.54 (m, 2H), 7.69-7.74 (m, 2H). HRMS: calcd for C₃₀H₃₅FSNO₅(M+H⁺) 540.2215, found 540.2228.

Step 2: 3-(methylsulfonyl)benzaldehyde

A solution of [3-(methylsulfonyl)phenyl]methanol (680 mg, 3.66 mmol) inanhydrous CH₂Cl₂ (20 mL) was treated with PCC (1.03 g, 4.75 mmol) atroom temperature for 2 hours. The solvent was removed and the residuewas purified by flash column chromatography (20-60% EtOAc in hexanes) togive the product (500 mg, 74% yield). ¹H NMR (300 MHz, CDCl₃) δ: 3.13(s, 3H), 7.77-7.82 (m, 1H), 8.18-8.24 (m, 2H), 8.46-8.48 (m, 1H), 10.12(s, 1H).

Step 1: [3-(methylsulfonyl)phenyl]methanol

A solution of 3-(methylsulfonyl)benzoic acid (1.0 g, 5.0 mmol) inanhydrous THF (25 mL) was treated with BH₃.THF (1 M solution, 7.5 mL) atroom temperature. The reaction was stirred for 12 hours before it wasquenched by slow addition of MeOH. The solvent was removed and theresidue was purified by flash column chromatography (0-5% MeOH inCH₂Cl₂) to give the product (0.84 g, 90% yield). ¹H NMR (300 MHz, CDCl₃)δ: 3.06 (s, 3H), 4.81 (d, J=6.0 Hz, 2H), 7.54-7.59 (m, 1H), 7.65-7.68(m, 1H), 7.85-7.88 (m, 1H), 7.96 (s, 1H).

Example A(102)2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), where4-chloro-1-methyl-1H-pyrazole-3-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300 MHz, DMSO-d₆)δ: 1.46-1.78 (m, 8H), 1.88 (s, 6H), 2.21-2.26 (m, 2H), 2.52-2.60 (m,1H), 2.78-2.94 (m, 4H), 3.57-3.60 (m, 2H), 3.72 (s, 3H), 7.24-7.31 (m,2H), 7.51-7.56 (m, 1H), 7.92 (s, 1H). Anal. Calcd. ForC₂₇H₃₁FClN₃O₃.1.0H₂O: C, 62.60; H, 6.42; N, 8.11. Found: C, 62.36; H,6.44; N, 8.47.

Example A(103)2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazol-1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), whereimidazo[1,2-a]pyridine-2-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300 MHz, DMSO-d₆)δ: 1.23-1.58 (m, 8H), 1.60 (s, 6H), 1.82-1.90 (m, 2H), 2.19-2.29 (m, 2H)2.46-2.66 (m, 3H), 3.50-3.63 (m, 2H), 6.76 (t, J=6.31 Hz, 1H), 6.87 (d,J=8.29 Hz, 1 H), 7.12 (m, 3H), 7.32 (d, J=9.04 Hz, 1H), 7.51 (s, 1H),8.34 (d, J=6.22 Hz, 1H). Anal. Calcd. For C₃₀H₃₂FN₃O₃.0.5H₂O: C, 70.57;H, 6.51; N, 8.23. Found: C, 70.73; H, 6.55; N, 7.85.

Step 1: Imidazo[1,2-a]pyridine-2-carbaldehyde

The title compound was prepared as described in the following reference:J. Heterocycl. Chem.; 1992; 691-697.

Example A(104)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97), where[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in placeof 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in final step of thatexample. ¹H NMR (400 MHz, CDCl₃) δ: 1.47-1.71 (m, 8H), 1.75 (s, 6H),2.00 (m, 2H), 2.39 (m, 1H), 2.66 (dd, J=103, 18 Hz, 2H), 2.69 (m, 2H),4.12 (s, 2H), 6.88 (d, J=12.9 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.20 (m,1H), 7.84 (t, J=8.1 Hz, 1H), 8.85 (m, 2H). MS (ESI): 504.1(M+H⁺).

Example A(105)(+)-2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The title compound was isolated by chiral chromatography of racemicmaterial described in Example A(104). Conditions: Chiralpak OJ-RH,150×4.6 mm, 0.6 mL/min, 30° C.; 35% acetonitrile, 65% water, 0.1% formicacid; retention time 17.6 min.

Example A(106)(−)-2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile

The title compound was isolated by chiral chromatography of racemicmaterial described in Example A(104). Conditions: Chiralpak OJ-RH,150×4.6 mm, 0.6 mL/min, 30° C.; 35% acetonitrile, 65% water, 0.1% formicacid; retention time 21.7 min.

Example A(107)2-(4-{2-[2-Cyclopentyl-5-(5-methyl-3H-imidazol-4-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97), where5-Methyl-3H-imidazole-4-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in the final step of thatexample. ¹H NMR (400 MHz, CDCl₃) δ: 1.47-1.71 (m, 8H), 1.70 (s, 6H),1.88 (m, 2H), 2.12 (s, 3H), 2.28 (m, 1H), 2.43 (d, J=103, 17.4 Hz, 1H),2.50 (m, 2H), 2.58 (m, 3H), 7.02 (d, J=6.57 Hz, 1H), 7.11 (d, J=13.1 Hz,1H), 7.34 (t, J=8.6 Hz, 1H), 7.78 (s, 1H). MS (ESI): 467.1 (M+H⁺).

Example A(108)2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97), where6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in the finalstep of that example. ¹H NMR (400 MHz, CDCl₃) δ: 1.48-1.71 (m, 8H), 1.76(s, 6H), 2.00 (m, 2H), 2.06 (s, 1H), 2.10 (s, 1H), 2.38 (m, 1H), 2.39(s, 3H), 2.68 (m, 2H), 2.81(m, 1H), 4.09 (s, 2H), 6.86 (d, J=12.9 Hz,1H), 6.92 (d, J=8.1 Hz, 1H), 7.84 (t, J=8.1 Hz, 1H), 8.63 (s, 1H), 8.70(s, 1H). MS (ESI): 518.6(M+H⁺).

Step 2: Preparation of 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

A mixture of (6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol(15.7g, 95.6 mmol), TEMPO (1.12 mg, 7.2 mmol), iodobenzene diacetate (33.9 g,105.2 mmol) in CH₂Cl₂ (100 mL) was stirred at room temperature for 2hours. Once the reaction was deemed complete, methyl-tert-butyl ether(50 mL) was added slowly to precipitate the product. The concentratedmother liquor was introduced into a silica gel column and eluted with 2%MeOH/CH₂Cl₂ to give additional amount of the aldehyde product as a whilesolid (12 g, 80%). ¹H NMR (300 MHz, CDCl₃) δ: 2.54 (m, 3H), 8.73 (m,1H), 8.85 (m, 1H), 10.23 (m, 1H). MS (APCI, M+H+): 163.1.

Step 1: Preparation of(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol

To a solution of (3-amino-1H-1,2,4-triazol-5-yl)methanol (16.6 g, 87.6mmol) in acetic cid was added 3-ethoxymethacrolein (10.0 g, 87.6 mmol),and the mixture was heated to 80° C. for 4 hours. Upon cooling of thereaction, the product crystallized out of solution. The collectedproduct was a white solid (14.0 g, 92%). ¹H NMR (300 MHz, DMSO-D6) δ:2.38 (m, 3H) 4.63 (m, 2H) 5.52 (m, 1H) 8.75 (m, 1H) 9.21 (m, 1H). MS(APCI, M+H+): 163.1, 165.1.

Example A(109)(+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was isolated by chiral chromatography of racemicmaterial described in Example A(108). Conditions: Chiralpak AS-RH,150×4.6 mm, 0.6 mL/min, 30° C.; 40% acetonitrile, 60% water, 0.1% formicacid; retention time 24.5 min.

Example A(110)(−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was isolated by chiral chromatography of racemicmaterial described in Example A(108). Conditions: Chiralpak AS-RH,150×4.6 mm, 0.6 mL/min, 30° C.; 40% acetonitrile, 60% water, 0.1% formicacid; retention time 17.99 min.

Example A(111):2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97), where6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in the finalstep of that example. ¹H NMR (400 MHz, CDCl₃) δ: 1.47-1.71 (m, 8H), 1.75(s, 6H), 2.00 (m, 2H), 2.39 (m, 1H), 2.65 (dd, J=101, 17.9 Hz, 2H), 2.68(m, 2H), 4.11 (m, 2H), 6.87 (d, J=11.6 Hz, 1H), 6.93 (d, J=6.6 Hz, 1H),7.35 (t,J=8.3 Hz, 1H), 8.79 (s, 1H), 8.88 (s, 1H). MS (ESI):539.1(M+H⁺).

Step 2: Preparation of Compound6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

A mixture of (6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol(9.86 g, 53.4 mmol), TEMPO (626 mg, 4.01 mmol), iodobenzene diacetate(18.9 g, 58.76 mmol) in CH₂Cl₂ (75 mL) was stirred at room temperaturefor 2 hours. Once the reaction was deemed complete, methyl-tert-butylether (50 mL) was added slowly to precipitate the product. as a whilesolid (8.72 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ: 8.93 (d, J=2.45 Hz, 1H),8.99 (d, J=2.64 Hz, 1H), 10.25 (s, 1H).

MS (APCI): 183.0, 185.0 (M+H⁺).

Step 1: Preparation of Compound(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol

To a slurry of (3-amino-1H-1,2,4-triazol-5-yl)methanol (28.5 g, 150mmol) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). Themixture was heated to 80° C. for 4 hours. Upon cooling of the reactionto room temperature, the product crystallized out as a white solid (25.5g, 92%). ¹H NMR (300 MHz, DMSO-D6) δ: 4.67 (s, 2H), 5.62 (s, 1H), 8.94(d, J=2.45 Hz, 1H), 9.81 (d, J=2.45 Hz, 1H). MS (APCI): 185.0 (M+H⁺).

Example A(112)2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile

A solution of2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl)-2-ethyl-butyronitrile(300 mg, 0.75 mmol) in anhydrous MeOH (3.0 mL) was treated with5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (198 mg,1.1 mmol), followed by borane-dimethylamine complex (62 mg, 1.05 mmol)at room temperature. The reaction was stirred for 12 hours before it wasquenched by the addition of CH₂Cl₂ (30 mL) and Amberlite IR 120(plus) (3g). The reaction was stirred for 30 minutes, and then filtered. Thefiltrate was concentrated to an oil, dissolved in CH₂Cl₂ (25 mL, andthen washed with 10 mL 1 N HCl. The aqueous layer was extracted with2×25 mL CH₂Cl₂. The organic layers were combined and dried over Na₂SO₄.After removing the solids by filtration, the liquid was concentrated toan oil. The desired product was isolated by preparatory HPLC (76 mg,18%). ¹H NMR (400 MHz, CDCl₃) δ: 0.74 (t, J=7.45 Hz, 6H), 1.37-1.59 (m,8H), 1.79-1.88 (m, 4H), 1.94-2.03 (m, 2H), 2.21 (t, J=8.84 Hz, 3H), 2.36(d, J=17.94 Hz, 1H), 2.47-2.55 (m, 5H), 2.59-2.63 (m, 4H), 3.95 (d,J=3.54 Hz, 2H), 6.66 (dd, J1=13.26 Hz, J2=1.64 Hz, 1H), 6.72-6.75 (m,2H), 7.23 (t, J=8.21 Hz, 1H).

Step 2: Preparation of Compound2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to step 4 of Example A(97),substituting2-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrilefrom step 1 below in place of1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile.¹H NMR (CDCl₃) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62-1.90 (br, 8H), 2.03-2.17(br, 4H), 2.20-2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75-2.82 (m,2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd,J=13.01, 1.64 Hz, 1H), 7.04 (dd, J=7.83, 1.77 Hz, 1H), 7.57 (t, J=8.21Hz, 1H).

Step 1: Preparation of Compound2-(4-bromo-2-fluoro-phenyl)-2-ethyl-butryonitrile

The desired product was prepared analogously to step 2 of Example A(97),substituting bromoethane in place of Mel. MS (APCI): 270 (M+H⁺).

Example A(113)1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

A solution of1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) atroom temperature. The reaction was stirred for 1 hour before it wascooled to −10° C. for 2 hours. The precipitate was removed byfiltration, and the filtrate was concentrated to an oil. The oil waspurified by flash chromatography (50 g SiO₂, 1:3->1:0 (93.5% ethylacetate, 6% methanol, 0.5% acetic acid): (81.5% hexanes, 12% ethylacetate, 6% methanol, 0.5% acetic acid)) to give the desired product asan oil. It was further purified by crystallization from ethylacetate/hexanes to give a white powder (146 mg, 18%). ¹H NMR (400 MHz,CDCl₃) δ: 1.41-1.64 (m, 8H), 1.84-1.88 (m, 2H), 2.22-2.28 (m, 2H), 2.42(s, 3H), 2.49-2.59 (m, 4H), 2.65-2.74 (m, 3H), 3.97-4.05 (m, 2H),6.72-6.82 (m, 2H), 7.05-7.10 (m, 1H), 8.55 (s, 1H), 8.67 (s, 1H).

Step 2: Preparation of Compound1-4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

The desired product was prepared analogously to step 4 of Example A(97),substituting1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile[prepared analogously to step 3 of Example A(97) substituting1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile)] in place of2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (CDCl₃) δ: 1.27-1.30 (m, 2H), 1.51-1.73 (m, 10H), 1.84-1.89 (m,2H), 2.19 (p, J=8.08 Hz, 1H), 2.58-2.71 (m, 4H), 3.36 (d, J=4.04 Hz,2H), 6.81-6.86 (m, 2H), 7.16-7.18 (m, 1H). MS (ESI): 368 (M−H).

Step 1: Preparation of Compound1-(4-Bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile

The desired product was prepared analogously to step 2 of Example A(97),substituting 1,2-bromoethane in place of Mel. ¹H NMR (400 MHz, CDCl₃):1.15 (dd, J=5.31, 2.27 Hz, 2H), 1.48 (dd, J=5.05, 2.53 Hz, 2H),6.97-7.12 (m, 3H).

Example A(114) 1{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

A solution of1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (296 mg, 2.0 mmol),followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at roomtemperature. The reaction was stirred for 1 hour and then wasconcentrated to an oil. The oil was purified by flash chromatography (50g SiO₂, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5% hexanes)to give the desired product as an oil. It was further purified bycrystallization from ethyl acetate/hexanes to give a white powder (142mg, 18%). ¹H NMR (400 MHz, CDCl₃) δ: 1.11-1.18 (m, 2H), 1.31-1.52 (m,10H), 1.75-1.80 (m, 2H), 2.16 (t, J=8.84 Hz, 1H), 2.34 (d, J=17.68 Hz,1H), 2.46 (t, J=7.83 Hz, 2H), 2.59 (d, J=17.94 Hz, 1H), 3.94 (d, J=3.79Hz, 2H), 6.62-6.70 (m, 2H), 6.97 (t, J=7.83 Hz, 1H), 7.02-7.04 (m, 1H),6.82-6.85 (m, 2H).

Example A(115)1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

A solution of1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (365 mg, 2.0mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) atroom temperature. The reaction was stirred for 1 hour and then wasconcentrated to an oil. The oil was purified by flash chromatography (50g SiO₂, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5%hexanes). The resultant oil was further purified by flash 509 SiO₂,1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5%hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid) to give thedesired product as an oil. It was further purified by crystallizationfrom ethyl acetate/hexanes to give a white powder (48.6 mg, 6%). ¹H NMR(400 MHz, CDCl₃) δ: 1.19-1.24 (m, 2H), 1.39-1.61 (m, 10H), 1.83-1.87 (m,2H), 2.25 (t, J=8.59 Hz, 1H), 2.38 (d, J=17.94 Hz, 1H), 2.54 (t, J=7.71Hz, 2H), 2.64 (d, J=17.94 Hz, 1H), 3.98 (d, J=5.56 Hz, 2H), 6.71-6.77(m, 2H), 7.06 (t, J=7.83 Hz, 1H), 8.66 (s, 1H), 8.73 (s, 1H).

Example A(116)(+)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The desired compound was separated from racemic2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile(100 mg) using chiral HPLC (Chiralpak AS-RH, 150×4.6 mm, 0.6 mL/min, 50%CAN, 50% H₂O, 30° C.). (40 mg, 80% recovery, 14.743 min retention time).

Step 1: Preparation of (+/−)2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

To a solution of2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile(0.40 g, 1.1 mmol) in MeOH (7 mL) was added5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g,1.08 mmol) and borane-dimethylamine complex (76 mg, 1.3 mmol) andstirred at room temperature for 3 hours. The reaction was quenched with10 mL saturated NH₄Cl and 5 mL water. To this was added 20 mL CH₂Cl₂ andthe pH of the aqueous phase was adjusted to 3. The layers wereseparated, and the aqueous layer was extracted with 3×30 mL 10% MeOH inCH₂Cl₂. The organic layers were combined, and dried over Na₂SO₄. Afterfiltering off the solids, the liquid was concentrated by rotaryevaporation to an oil. The oil was flash chromatographed, and theresulting product was further purified by preparatory HPLC. Yield: 28mg, 5%. MS (ESI): 530 (M−H).

Example A(117)(−)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The desired compound was separated from racemic2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile(100 mg) using chiral HPLC (Chiralpak AS-RH, 150×4.6 mm, 0.6 mL/min, 50%CAN, 50% H₂O, 30° C.). (38 mg, 76% recovery, 7.536 min retention time).

Example A(118)2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile

The desired product was prepared analogously to step 4 of Example A(97),substituting2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-methyl-propionicacid methyl ester in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (300 MHz, CDCl₃) δ: 1.30-1.74 (m, 16H), 1.82-1.84 (m, 1H),2.50-2.65 (m, 4H), 3.31 (s, 2H), 3.56 (s, 3H), 6.71 (t, J=10.0 Hz, 1H),7.08-7.21 (m, 2H). MS(ESI): 403(M−H).

Step 3:2-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-4H-1,3-dioxin-4-yl)-3-hydroxybut-1-2-fluoro-phenyl]-2-methyl-propionicAcid Methyl Ester

The desired product was prepared analogously to step 3 of Example A(97),substituting 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionic acid methylester in place of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile. ¹HNMR (CDCl₃) δ: 1.48 (s, 6H), 1.48-1.76 (m, 14H), 2.16-2.18 (m, 1H), 2.54(s, 1H), 2.58 (d, J=2.8 Hz, 2H), 3.60 (s, 3H), 5.39 (s, 1H), 6.97-7.21(m, 3H). MS(ESI): 457 (M−H).

Step 2: 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionic Acid Methyl Ester

The desired product was prepared analogously to step 2 of Example A(97).¹H NMR (300 MHz, CDCl₃) δ: 1.47 (s, 6H), 3.65 (s, 3H), 7.11-7.23 (m,3H).

Step 1: Preparation of Compound (4-Bromo-2-fluoro-phenyl)-acetic AcidMethyl Ester

MeOH (16 mmol, 0.81 ml), TMSCI (20 mmol, 2.13 g) and(4-bromo-2-fluorophenyl) acetonitrile (10 mmol, 2.13 g) weresequentially added to a dry flask under a nitrogen atmosphere at roomtemperature. The reaction mixture was heated at 50° C. for 4 hours.After being cooled to room temperature, water (20 mmol, 0.36 ml) wasadded to the mixture, followed by the addition of Na₂CO₃ (10 mmol, 1.06g) and CH₂Cl₂ (10 ml). Drying over MgSO₄ and concentrating at lowpressure afforded product (0.85 g, 35% yield). ¹H NMR (300 MHz, CDCl₃)δ: 3.57 (s, 2H), 3.65 (s, 3H), 7.08 (t, J=8.3 Hz, 1H), 7.16-7.21 (m,2H).

Example A(119)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

A solution of6-Cyclopentyl-6-{2-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(270 mg, 0.73 mmol) in anhydrous MeOH (7.0 mL) was treated with1H-pyrazole-4-carbaldehyde (122 mg, 1.46 mmol), followed by addition ofborane-dimethylamine complex (62 mg, 1.05 mmol) at room temperature. Thereaction was stirred for 12 hours before it was quenched by the additionof 1 N HCl. The mixture was extracted with 10% MeOH in CH₂Cl₂ (3×10 mL),and the combined organic layers were washed with brine, then dried overMgSO₄. The solvent was removed, and the residue was purified bychromatography (80:14:6:0.5 of EtOAc:Hexane:MeOH:Acetic acid) to givethe product (23 mg, 6.5% yield). ¹H NMR (CDCl₃) δ: 1.19-1.69 (m, 10H),2.61 (s, 3H), 2.79 (s, 3H), 3.40-3.43 (m, 1H), 3.6-3.64 (m, 2H),3.80-3.84 (m, 2H), 4.19-4.24 (m, 2H), 5.03 (m, 2H), 6.88 (s, 1H),7.15-7.18 (m, 1H), 7.50-7.55 (m, 1H), 7.70-7.73 (m, 1H). MS(ESI): 507(M−H).

Example A(120)6-Cyclopentyl-6-2-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The desired product was prepared analogously to step 4 of Example A(97),substituting6-{2-Cyclopentyl-4-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-2-hydroxy-butyl}-2,2-dimethyl-[1,3]dioxin-4-onein place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (CDCl₃) δ: 1.20 (t, J=6.95 Hz, 1H), 1.41-1.79 (m, 7H), 1.87-2.00(m, 2H), 2.26 (m, 1H), 2.65 (t, J=8.34 Hz, 2H), 2.75 (d, J=2.53 Hz, 2H),2.87 (t, J=6.44 Hz, 2H), 3.41 (d, J=2.27 Hz, 2H), 3.47 (q, J=7.07 Hz,1H), 3.84 (t, J=6.57 Hz, 1H), 6.82 (d, J=10.86 Hz, 1H), 6.86 (d, J=7.58Hz, 1H), 7.15 (t, J=7.71 Hz, 1H). MS (ESI): 347 (M−H).

Step 3:6-{2-Cyclopentyl-4-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-2-hydroxy-but-3-ynyl}-2,2dimethyl-[1,3]dioxin-4-one

The desired product was prepared analogously to step 3 of Example A(97),substituting 2-(4-Bromo-2-2-fluoro-phenyl)-ethanol in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile. ¹H NMR (CDCl₃) δ:1.25 (t, J=7.20 Hz, 1H), 1.36-1.41 (m, 2H), 1.55-1.60 (m, 3H), 1.65-1.70(m, 3H), 1.71 (s, 3H), 1.72 (s, 3H), 1.78-1.83 (m, 2H), 2.90 (t, J=6.44Hz, 2H), 3.47 (q, J=6.99 Hz, 1H), 3.85 (t, J=6.57 Hz, 2H), 5.45 (s, 1H),7.04 (d, J=10.11 Hz, 1H), 7.09 (d, J=7.83 Hz, 1H), 7.19 (t, J=7.58 Hz,1H). MS (ESI): 401 (M−H).

Step 2: 2-(4-Bromo-2-2-fluoro-phenyl)-ethanol

In a dried flask equipped with a reflux condenser and an argon line,2-(4-Bromo-2-fluoro-phenyl)-acetic acid (1.35 g, 5.78 mmol) wasdissolved in THF. To this solution, a solution of 1MBH₃.THF (11.57 ml,11.57 mmol) was added at 0° C. for 4 hours. The reaction mixture wasdiluted with cold water (15 ml), washed with a saturated solution ofNaHCO₃ (15 ml), and extracted with ether (3×20 ml). The combined organiclayers were washed with brine and dried over MgSO₄. The solvent wasremoved, and the residue was purified by flash column chromatography(1-50% EtOAc in Hexane) to give the product (0.52 g, 41.0% yield). ¹HNMR (CDCl₃) δ: 2.80(t, J=6.0 Hz, 2H), 3.78 (t, J=6.5 Hz, 2H), 7.06 (t,J=8.4 Hz, 1H), 7.14-7.18 (m, 2H).

Step 1: 2-(4-Bromo-2-2-fluoro-phenyl)-acetic Acid

A mixture of (4-bromo-2-fluorophenyl)acetonitrile (8.55 g, 40 mmol) fromstep 1 in Example A (97); Potassium hydroxide (11.52 g, 320 mmol);Ethanol (80 ml) and water (16 ml) was heated at 70° C. for 24 hours. Themixture was then diluted with water (50 ml), and subsequently extractedwith ether (3×75 ml). The pH of the aqueous layer was adjusted toapproximately 3 with dropwise addition of 1N H₂SO₄. After the aqueouslayer was extracted with ether (3×125 ml), the combined organic layerswere washed with brine and dried over MgSO₄. The solvent was removed togive product (4.50 g, 48% yield). ¹H NMR (CDCl₃) δ: 3.60 (s, 2H),7.07-7.22 (m, 3H).

Example A(121)6-Cyclopentyl-6-{2-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The desired product was prepared analogously to step 4 of Example A(97),substituting6-{2-Cyclopentyl-4-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-2-hydroxy-butyl}-2,2-dimethyl-[1,3]dioxin-4-one(1.70 g, 3.91 mmol) in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (CDCl₃) δ: 1.35 (s, 6H), 1.52-1.78 (m, 8H), 1.90-1.99 (m, 2H),2.27 (m, 1H), 2.65 (t, J=8.34 Hz, 2H), 2.74 (d, J=2.27 Hz, 2H), 3.40 (d,J=1.77 Hz, 2H), 3.75 (s, 2H), 6.80 (dd, J=13.64, 1.77 Hz, 1H), 6.88 (dd,J=8.08, 1.77 Hz, 1H), 7.22 (d, J=8.59 Hz, 1H). MS (ESI): 375 (M−H).

Step 3:6-{2-Cyclopentyl-4-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-2-hydroxy-but-3-ynyl}-2,2-dimethyl-[1,3]dioxin-4-one)

The desired product was prepared analogously to step 3 of Example A(97),substituting 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-1-ol in placeof 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile. ¹H NMR (CDCl₃) δ:1.35 (s, 6H), 1.48-1.62 (m, 5H), 1.71 (s, 3H), 1.72 (s, 3H), 1.77-1.87(m, 2H), 2.20 (m, 1H), 2.61 (s, 1H), 2.64 (d, J=3.03 Hz, 2H), 3.76 (d,J=5.56 Hz, 2H), 5.44 (s, 1H), 7.01 (d, J=12.88 Hz, 1H), 7.10 (d, J=8.08Hz, 1H), 7.26 (m, 1H).

MS (ESI): 429(M−H).

Step 2: 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-1-ol

To a solution of 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde(1.37 g, 5.58 mmol) in MeOH (18 ml) at 0° C. was added NaBH₄ (0.21 g,5.58 mmol). After being stirred for 2 hours at 0° C., the mixture wasallowed to warm to room temperature. The reaction mixture was dilutedwith water (20 ml) and extracted with ether (3×75 ml). The combinedorganic layers were dried over MgSO₄. The solvent was removed, and theresidue was purified by flash column chromatography (15-35% EtOAc inHexane) to give the product (1.10 g, 80.0% yield). ¹H NMR (CDCl₃) δ:1.23 (s, 1H) 1.35 (s, 3H) 1.35 (s, 3H) 3.75 (d, J=1.26 Hz, 2H) 7.17 (d,J=2.27 Hz, 1H) 7.20 (d, J=3.03 Hz, 1H) 7.22 (m, 1H).

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde

DIBAL-H (14 ml, 14.0 mmol) was added slowly to a solution of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile (2.42 g, 10 mmol) inCH₂Cl₂ (10 ml) at 0° C., and the reaction mixture was stirred for 4hours. To the reaction was added 10 ml of 1N HCl (10 ml). The layerswere separated, and the aqueous layer was extracted with 3×50 ml ether.The combined organics were washed with 10 ml H₂O, and then dried overMgSO₄. After filtering off the solids, the mother liquor wasconcentrated to the desired product by rotary evaporation (1.56 g, 64%yield). ¹H NMR (CDCl₃) δ: 1.29 (s, 6H), 7.05-7.26 (m, 3H), 9.53 (s, 1H).

Example A(122)6-Cyclopentyl-6-[2-(3,5-difluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The desired product was prepared analogously to Example A(97),substituting 1-Bromo-3,5-difluoro-benzene in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile in step 2 of thatexample. ¹H NMR (CDCl₃, 300 MHz) δ: 1.40-1.75 (m, 8H), 1.82-2.12 (m,2H), 2.25-2.74 (m, 1H), 2.67-2.81 (m, 4H), 3.45-3.59 (m, 2H), 6.82-6.94(m, 1H), 6.95-7.06 (m, 1H), 7.25 (dd, J=8.40, 1.70 Hz).

Example A(123)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.2 g,0.57 mmol) was added to a solution of6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(0.2 g, 0.53 mmol) in MeOH (6 mL). The reaction mixture was stirred for15 mins and then treated with borane-dimethylamine complex (50 mg, 0.86mmoL). After 15 hours the reaction mixture was quenched with 1N HCl andextracted with 10% MeOH in CH₂Cl₂. The combined organic layers wereconcentrated and recrystallized from EtOAc to give the product as awhite soild (0.15 g, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.09 (t, J=7.3Hz, 3H), 1.43-1.72 (br m, 8H), 2.05-2.17 (m, 2H), 2.43 (m, 1H),2.48-2.58 (m, 10H), 2.66 (d, J=17.4 Hz, 1H), 2.81 (d, J=17.4 Hz, 1H),3.74 (d, J=16.2 Hz, 1H), 3.85 (d, J=16.2 Hz, 1H), 6.76 (s, 1H), 6.84 (d,J=11.6 Hz, 1H) 7.07 (s, 1H), 9.08 (s, 1H), 11.01 (s, 1H). MS:C₂₈H₃₂N₄O₄F (M+H⁺) 509.10.

Example A(124)6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(97) whereacetic acid 4-bromo-2-ethyl-6-fluoro-phenyl ester (from step 4 below)was substituted in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile in that example. ¹HNMR (400 MHz, CDCl₃) δ: 1.21 (t, J=7.6 Hz, 3H), 1.44-1.75 (m, 8H), 1.92(m, 2H), 2.27 (m, 1H), 2.58 (m, 2H), 2.64 (q, J=7.6 Hz, 2H), 2.76 (m,2H), 3.43 (s, 2H), 5.04 (s, 1H), 6.68 (s, 1H), 6.71 (d, J=10.6 Hz, 1H).Anal. Calcd. For C₂₀H₂₅O₄F: C, 68.95; H, 7.23. Found: C, 68.71; H, 7.28.

Step 4: Preparation of Compound Acetic Acid4-bromo-2-ethyl-6-fluoro-phenyl Ester

Acetyl chloride (0.39 mL, 5.5 mmol) followed by triethylamine (0.76 mL,5.5 mmol) were added to a cooled 0° C. solution of2-ethyl-6-fluoro-phenol (1 g, 4.5 mmol, from step 3) dissolved in CH₂Cl₂(10 mL). The reaction was stirred for 2 hrs and then partitioned between1N HCl and EtOAc. The organic layer was washed with saturated NaHCO₃,brine, dried over Na₂SO₄ and concentrated to a yellow oil. The oil waspurified by silica gel chromatography (0% to 5% EtOAc in hexanes) togive the title compound as a clear oil (1 g, 84%). ¹H NMR (400 MHz,CDCl₃): δ 1.18 (t, J=7.6 Hz, 3H), 2.35 (s, 3H), 2.54 (q, J=7.6 Hz, 2H),7.18 (m, 2H).

Step 3: Preparation of Compound 4-Bromo-2-ethyl-6-fluoro-phenol

A solution of tetrabutyl ammonium tribromide (4.2 g, 8.6 mmol) in CHCl₃(25 mL) was added to a stirred solution of 2-ethyl-6-fluoro-phenol (1.1g, 7.9 mmol) dissolved in CHCl₃ (25 mL). The reaction mixture wasstirred for 24 hrs and then quenched with 5% solution of sodiumthiosulfate (30 mL). The biphasic mixture was stirred for 30 mins andthen the layers were separated. The organic layer was washed with 1NHCl, saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated. Thecrude residue was purified by flash column chromatography (0-10% EtOAcin hexanes) to give the desired product (1 g, 60%). ¹H NMR (400 MHz,CDCl₃): δ 1.21 (t, J=7.6 Hz, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.09 (d, J=4.8Hz, 1H), 7.06 (s, 1H), 7.09 (d, J=11.9 Hz, 1H).

Step 2: Preparation of Compound 2-Ethyl-6-fluoro-phenol

A mixture of 2-fluoro-6-(1-hydroxy-ethyl)-phenol (1.7 g, 10.9 mmol) and10 wt % Pd/C (0.85 g, Degussa type) in MeOH (30 mL) was stirred under aballoon of H₂ for 6 hours. The reaction mixture was filtered through apad of celite washing with EtOAc. The filtrate was concentrated to ayellow oil (1.35 g, 87%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (t, J=7.6 Hz,3H), 2.68 (q, J=7.3 Hz, 2H), 5.12 (s, 1H), 6.76 (m, 1H), 6.92 (m, 2H).

Step 1: Preparation of Compound 2-Fluoro-6-(1-hydroxy-ethyl)-phenol

Methyl lithium (25.5 mL, 35.7 mmol, 1.4M in ether) was added to a cooled−78° C. solution of 3-fluorosalicylaldehyde (2 g, 14.3 mmol) dissolvedin THF (50 mL). The reaction mixture was stirred for 3 hours and thenwarmed up to room temperature. After 3 hours the reaction was quenchedwith saturated NH₄Cl and extracted with EtOAc. The organic extracts werewashed with 1N HCl, brine, dried over Na₂SO₄ and concentrated to an oil.The oil was purified by flash column chromatography (0% to 20% EtOAc inhexanes) to give the title compound as a clear oil (2.2 g, 99%). ¹H NMR(400 MHz, CDCl₃): δ 1.58 (d, J=6.6 Hz, 3H), 2.68 (s, 1H), 5.13 (m, 1H),6.78 (td, J=7.8, 4.8 Hz, 1H), 6.87 (d, J=7.6, 1H), 6.99 (m, 1H), 7.33(s, 1H).

Example A(125)6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123), where6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.14 (t, J=7.6 Hz, 3H), 1.41-1.75 (m, 8H), 2.13(m, 2H), 2.41 (s, 3H), 2.44 (m, 1H), 2.47-2.62 (m, 4H), 2.72 (d, J=17.7Hz, 1H), 2.82 (d, J=17.7 Hz, 1H), 3.78 (d, J=16.2 Hz, 1H), 3.86 (d,J=16.2 Hz, 1H), 6.80 (s, 1H), 6.86 (d, J=11.6 Hz, 1H), 8.74 (s, 1H),8.90 (s, 1H), 9.13 (s, 1H), 10.93 (s, 1H). MS: C₂₇H₃₁N₄O₄F (M−H) 493.20.

Example A(126)6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

A solution of6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(150 mg, 0.45 mmol) in anhydrous MeOH (3.0 mL) was treated with6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (120 mg, 0.73mmol), followed by borane-dimethylamine complex (40 mg, 0.68 mmol) atroom temperature. The reaction was stirred for 5 hours before it wasquenched by the addition of 0.5N HCl (25 mL). The mixture was extractedwith 10% MeOH in CH₂Cl₂ (3×10 mL) and the combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by crystallization from EtOAc/Hexanes to give theproduct as a white solid (75 mg, 35% yield). ¹H NMR (300 MHz, DMSO-d₆)δ: 1.08 (t, J=7.3 Hz, 3H), 1.67 (m, 8H), 2.07 (m, 2H), 2.36 (s, 3H),2.47 (m, 7H), 2.76 (m, 1H), 3.81 (q, J=7.3 Hz, 2H), 6.70 (m, 3H), 8.66(s, 1H), 8.94 (s, 1H), 10.78 (s, 1H).

Step 1: Preparation of Compound6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

This compound was prepared analogously to example A(124), using2-ethylphenol in place of 2-Ethyl-5-fluorophenol. The result was an offwhite solid. ¹H NMR (300 MHz, CDCl₃): δ 1.22 (t, 3H, J=7.6 Hz),1.43-1.78 (m, 8H), 1.8-2.01 (m, 2H), 2.28 (m, 1H), 2.57-2.63 (m, 4H),2.76 (s, 2H), 3.42 (s, 2H), 4.63 (s, 1H), 6.68 (d, 1H, J=8.1 Hz), 6.84(d, 1H, J=8.1 Hz), 6.90 (s, 1H). Anal. Calcd. For C₂₀H₂₆O₄.0.25H₂O: C,71.72; H, 7.98. Found: C, 71.10; H, 7.99.

Example A(127)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

This compound was prepared analogously to example A(126), except that6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-Methyl-[1,2,4]triazolo[1,5-]pyrimidine-2-carbaldehyde. Theresult was a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ: 1.10 t, J=7.3 Hz,3H), 1.65 (m, 8H), 2.04 (m, 2H), 2.47 (m, 7H), 2.75 (m, 1H), 3.81 (q,J=7.3 Hz, 2H), 6.68 (m, 3H), 8.82 (s, 1H), 9.43 (s 1H), 10.83 (brs, 1H).

Example A(128)6-Cyclopentyl-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

This compound was prepared analogously to example A(124), using2-(4-Bromo-2-ethyl-phenoxy)-ethanol in place of2-Ethyl-4-bromo-6-fluorophenol. The result was an off white solid.

¹H NMR (300 MHz, CDCl₃): δ 1.19 (t, 3H, J=7.6 Hz), 1.43-1.98 (m, 11H),2.28 (m, 1H), 2.63 (m, 4H), 2.77 (s, 2H), 3.42 (s, 2H), 4.05 (m, 4H),6.77 (d, J=9.1 Hz, 1H), 6.93 (m, 2H).

Step 1: Preparation of Compound 2-(4-Bromo-2-ethyl-phenoxy)-ethanol

To a solution of 2-ethyl-4-bromophenol (3.5 g, 17.4 mmol) and ethylenecarbonate (3.22 g, 37 mmol) in NMP (60 mL) was added potassium carbonate(5.17 g, 37.4 mmol). The resulting mixture was heated to 125° C. andmaintained for 3 h. The reaction was cooled and poured into water (250mL) and extracted with EtOAc (2×100 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column chromatography (10-20% EtOAc inhexanes) to give the product (3.5 g, 82% yield) as a clear oil. ¹H NMR(300 MHz, CDCl₃) δ: 1.19 (t, J=7.6 Hz, 3H), 1.89 (brs, 1H), 2.61 (q,J=7.6 Hz, 2H), 4.05 (m, 4H), 6.70 (d, J=8.7 Hz, 1H), 7.24 (m, 2H).

Example A(129)6-Cyclopentyl-6-[2-(3-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

This compound was prepared analogously to example A(124), using4-Bromo-2-fluoro-phenol in place of 2-Ethyl-4-bromo-6-fluorophenol. Theresult was an off white solid. ¹H NMR (300 MHz, CDCl₃): δ: 1.42-1.78 (m,8H), 2.01 (m, 2H), 2.28 (m, 1H), 2.63 (m, 2H), 2.76 (s, 2H), 3.42 (s,2H), 4.63 (s, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 7.13(s, 1H).

Example A(130)6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

This compound was prepared analogously to example A(124), using4-Bromo-2-cyclopropyl-1-methoxy-benzene in place of2-Ethyl-4-bromo-6-fluorophenol. The result was an off white solid. ¹HNMR (300 MHz, CDCl₃): δ: 0.64 (m, 2H), 0.91 (m, 2H), 1.69 (m, 10H), 2.13(m, 1H), 2.26 (m, 1H), 2.57 (t, J=8.5 Hz, 2H), 2.76 (s, 2H), 3.41 (s,2H), 3.84 (s, 3H), 6.60 (s, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.1Hz, 1H).

Example A(131)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-I⁶-sulfanyl]amino}phenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.072 g,0.41 mmol) was added to a solution of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(0.14 g, 0.34 mmol) in MeOH (10 mL). The reaction mixture was stirredfor 15 mins and then treated with borane-dimethylamine complex (30 mg,0.51 mmoL). After 15 hours the reaction mixture was quenched withconcentrated HCl, and concentrated to a residual oil. Purification byflash column chromatography (EtOAc then 0%-5% MeOH in CH₂Cl₂) gave theproduct as a white solid (100 mg, 51%). ¹H NMR (CDCl₃): δ 1.40-2.24(brm, 1H), 2.60 (s, 3H), 2.73 (m, 5H); 2.94 (s, 3H), 3.10 (m, 5H),3.50(m, 2H), 3.74 (m, 1H), 6.77 (t, J=15.07 Hz, 1H), 6.95 (m, 2H), 7.05(m, 1H). Anal. Calcd. For C₂₈H₃₄O₅N₅SF: C, 58.83; H, 5.99, N, 12.25.Found: C, 58.94; H, 6.07, N, 12.13.

Example A(132)6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(97), whereN-(4-bromophenyl)-N-methylmethanesulfonamide (from step 1 below) wassubstituted in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile in step 3 of thatexample. ¹H NMR (CDCl₃): δ 1.40-1.80 (brm, 8H), 2.01-2.69 (m, 3H),2.78-2.83 (m, 3H), 2.94 (m, 4H), 3.10 (m, 5H), 6.77 (t, J=12.07 Hz, 1H),6.95 (d, J=2.09 Hz, 1H), 7.05 (m, 1H). Anal. Calcd. For C₂₀H₂₆O₅NSF: C,58.38; H, 6.37, N, 3.40. Found: C, 58.64; H, 6.46, N, 3.13.

Step 1: Preparation of CompoundN-(4-bromo-2-fluorophenyl)-N-methylmethanesulfonamide

Methane sulfonyl chloride (2.03 ml, 26 mmol) was added to a solution of4-bromo-2-fluoroaniline (5.0 g, 26 mmol) and pyridine (2.12 ml, 26 mmol)in dichloromethane (100 ml) at 0° C. The reaction mixture was stirredfor 1 hr, after which time it was partitioned between dichloromethane(100 ml) and 1N hydrochloric acid (100 ml). The organics were separatedand dried over magnesium sulfate, filtered and concentrated in vacuo toafford a yellow oil. The crude oil was dissolved in dimethylformamide(50 mL) and treated with potassium carbonate (5.1 g, 37.5 mmol) followedby methyl iodide (2.33 ml, 37.4 mmol). The reaction mixture was stirredfor 24 hrs after which time it was partitioned between diethylether (100ml) and water (100 ml). The aqueous was extracted further with diethylether (2×100 ml). The combined organics were dried over magnesiumsulfate, filtered and the solvent concentrated in vacuuo to afford thetitle compound as a brown oil (6.9 g). ¹H NMR (CDCl₃): δ 2.94 (s, 3H),3.10 (s, 3H), 6.77 (t, J=4.96 Hz, 1H), 6.95 (d, J=4.96 Hz, 1H), 7.05 (m,1H).

Example A(133)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-{methyl[methyl(dimethylene)-I⁶-sulfanyl]amino}phenyl)ethyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(131), whereN-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]phenyl}-N-methylmethanesulfonamide(from step 1 below) was substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione.¹H NMR (CDCl₃): δ 1.40-1.80 (brm, 8H), 2.05-2.20 (m, 4H), 2.62 (s, 3H),2.67 (m, 5H), 2.94 (s, 3H), 3.04 (m, 5H), 4.02 (s, 2H), 6.95 (m, 3H),7.24 (s, 2H). Anal. Calcd. For C₂₈H₃₅O₅N₅S: C, 60.74; H, 6.37, N, 12.65.Found: C, 61.04; H, 6.46, N, 12.33.

Step 1: Preparation of CompoundN-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]phenyl}-N-methylmethanesulfonamide

The title compound was prepared analogously to Example A(132), (where4-bromo-aniline was used in place of 4-bromo-2-fluoroaniline in thatexample. ¹H NMR (CDCl₃): δ 1.4-2.24 (brm, 11H), 2.60-2.89 (brm, 4H),2.94 (s, 3H), 3.04 (m, 5H), 6.96 (dd, J=4.96 Hz, 2H), 7.23 (dd, J=4.96Hz, 2H). Anal. Calcd. For C₂₀H₂₇NO₅S: C, 61.04; H, 6.91; N, 3.56. Found:C, 61.35; H, 6.94; N, 3.20.

Example A(134) Preparation of Compound6-cyclopentyl-6-{2-[4-(1,1-dioxidoisothiazolidin-2-yl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(97), where2-(4-bromo-2-fluorophenyl)isothiazolidine 1,1-dioxide (from step 2below) was substituted in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile of that example. ¹HNMR (CDCl₃): δ1.4-2.54 (brm, 12H), 2.80-2.99 (brm, 3H), 3.06 (m, 3H),3.50 (m, 2H), 4.00 (m, 2H), 6.86 (m, 2H), 7.03 (d, J=2.96 Hz, 1H). Anal.Calcd. For C₂₁H₂₆NO₅SF: C, 59.56; H, 6.19; N, 3.31. Found: C, 59.57; H,6.24; N, 3.20.

Step 2: Preparation of Compound2-(4-bromo-2-fluorophenyl)isothiazolidine 1,1-dioxide

N-(4-bromo-2-fluorophenyl)-3-chloropropane-1-sulfonamide (8.27 g,0.025M) and potassium carbonate (5.10 g, 0.0375M) was dissolved indimethylformamide (50 ml) at room temperature under an atmosphere ofnitrogen. The reaction mixture was stirred for a further 24 hrs afterwhich time it was partitioned between diethylether (500 ml) and water(500 ml). The organics were washed with 1N HCl (300 ml) and then water(100 ml) The organics were then dried over magnesium sulfate, filteredand the solvent concentrated in vacuuo to afford the title compound as abrown oil (9.0 g). ¹H NMR (CDCl₃): δ 2.40-2.50 (m, 2H), 3.25-3.40 (m,2H), 4.00 (m, 2H); 6.78 (m, 2H), 7.10 (d, J=2.56 Hz, 1H),).

Step 1: Preparation of CompoundN-(4-bromo-2-fluorophenyl)-3-chloropropane-1-sulfonamide

3-chloropropane-1-sulfonyl chloride (3.16 ml, 0.026M) was added to asolution of 4-bromo-2-fluoroaniline (5.00 g, 0.026M) and pyridine (2.12ml, 0.026M) in dichloromethane (100 ml) at 0° C. The reaction mixturewas stirred for 1 hr, after which time it was partitioned betweendichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organicswere separated and dried over magnesium sulfate, filtered andconcentrated in vacuuo to afford the title compound as a yellow oil (8.3g). ¹H NMR (CDCl₃): δ2.54 (m, 2H), 2.90 (m, 2H), 3.64 (d, J=2.56 Hz,2H), 6.91 (d, J=3.56 Hz, 1H), 7.07 (m, 2H).

Example A(135)6-cyclopentyl-6-[2-(3-cyclopentyl-4-hydroxyphenyl)ethyl]-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-on

The title compound was prepared analogously to Example A(131) where6-cyclopentyl-6-[2-(3-cyclopentyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(from step 1 below) was substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione¹H NMR (CDCl₃): δ 1.40-1.80 (brm, 16H), 2.20 (m, 3H), 2.58 (s, 3H), 2.73(m, 5H), 3.00 (m, 3H), 4.00 (s, 2H), 6.60 (d, J=2.07 Hz, 1H), 6.85 (d,J=2.07 Hz, 1H), 6.99 (s, 1H), 7.13 (s, 1H). Anal. Calcd. For C₃₁H₃₈O₄N₄:C, 70.16; H, 7.22, N, 10.56. Found: C, 70.54; H, 7.46, N, 10.13.

Step 1: Preparation of Compound6-cyclopentyl-6-[2-(3-cyclopentyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(124) where2-cyclopentyl phenol was used in place of 2-ethyl-5-fluorophenol in thatexample. ¹H NMR (CDCl₃): δ 1.43-1.85 (br m, 16H), 1.87-2.21, (m, 3H),2.70-3.18 (brm, 7H), 4.95 (s, 1H), 6.60 (d, J=8.1 Hz 1H), 6.84 (d, J=8.1Hz, 1H), 7.12 (s, 1H). MS(APCI): 369 (M−H).

Example A(136)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-hydroxy-3-propylphenyl)ethyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(131), where6-cyclopentyl-6-[2-(4-hydroxy-3-propylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(from step 1 below) was substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione.¹H NMR (CDCl₃): δ 1.00 (t, J=7.54 Hz, 3H), 1.40-1.80 (brm, 10H),2.00-2.18(m, 5H), 2.59 (s, 3H), 2.73 (m, 5H), 2.95 (m, 2H), 4.00 (s,2H), 6.67 (d, J=5.78 Hz, 1H), 6.95 (m, 2H), 7.21 (s, 1H). Anal. Calcd.For C₂₉H₃₆O₄N₄: C, 69.02, H, 7.19, N, 11.10. Found: C, 69.23; H, 7.43,N, 11.31.

Step 1:6-cyclopentyl-6-[2-(4-hydroxy-3-propylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(124), where2-propylphenol was used in place of 2-ethyl-5-fluorophenol in thatexample. ¹HNMR(CDCl₃): δ 1.00 (t, J=8.1 Hz 3H,), 1.33-1.85 (br m, 8H),1.87-2.01 (m, 2H), 2.22 (m, 3H), 2.30 (m, 2H), 2.60-3.10 (brm, 6H), 5.78(s, 1H), 6.70 (d, J=2.07 Hz 1H), 6.80 (s, 1H), 6.85 (d, J=2.07 Hz, 1H).MS (APCI): 343 (M−H).

Example A(137)6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-hydroxy-3-propylphenyl)ethyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(131), where6-cyclopentyl-6-[2-(4-hydroxy-3-propylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dioneand 5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(CDCl₃): δ 1.00 (t, J=7.54 Hz, 3H), 1.40-1.80 (brm, 16H), 2.00-2.18(m,5H), 2.59 (m, 2H), 2.73 (m, 4H), 2.95 (m, 2H), 4.00 (s, 2H), 6.67 (d,J=5.78 Hz, 1H), 6.95 (m, 2H), 7.21 (s, 1H). Anal. Calcd. For C₃₂H₄₀O₄N₄:C, 70.56; H, 7.40; N, 10.29. Found: C, 70.23; H, 7.69; N, 10.31.

Example A(138)6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(126), where5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(CDCl₃): δ 1.40-1.90 (brm, 17H), 2.09-2.40 (m, 5H), 2.60-2.80 (m, 6H),3.00 (m, 2H), 3.25 (m, 2H), 3.95 (m, 1H), 6.64 (d, J=5.21 Hz, 1H), 6.78(d, J=5.21 Hz, 1H), 7.00 (s, 1H), 7.22 (s, 1H). Anal. Calcd. ForC₃₀H₃₈O₄N₄: C, 69.47; H, 7.38; N, 10.80. Found: C, 69.54; H, 7.40; N,10.89.

Example A(139)N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide

The title compound was prepared analogously to Example A(131), whereN-(2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenoxy}ethyl)acetamide (from step 3 below) was substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione.¹H NMR (CDCl₃): δ 1.20 (t, J=9.54 Hz, 3H), 1.40-1.80 (brm, 10H),2.00-2.40 (m, 3H), 2.60 (m, 5H), 2.87 (m, 5H), 2.99 (m, 2H), 3.35 (t,J=6.24 Hz, 2H), 3.80 (t, J=6.24 Hz, 2H), 4.02 (s, 2H), 6.65 (m, 2H),6.95 (s, 1H), 6.99 (s, 1H).

Step 3: Preparation of CompoundN-(2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenoxy}ethyl)acetamide

To a solution of{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)but-1-ynyl]-2-ethylphenoxy}acetonitrile(1.90 g, 4.4 mmol) in EtOH (100 mL) was added Pd(OH)₂ (500 mg, 20 wt %).The mixture was stirred under H₂ for 3 hours before it was filteredthrough a pad of celite. The solvent was removed and the residue wastaken directly into next step without further purification.

The crude mixture was dissolved in dichloromethane (10 ml) and acetylchloride (0.041 ml, 0.579 mmol) followed by pyridine (0.046 ml, 0.579mmol) were added. The reaction mixture was stirred at room temperaturefor 12 hours, after which time the mixture was partitioned betweendichloromethane (100 ml) and 1N HCl (100 ml). The organics wereseparated, dried over sodium sulfate, filtered and concentrated invacuuo. The crude mixture was taken on directly to the next step withoutfurther purification.

The crude mixture was dissolved in anhydrous MeOH (20 mL) and treatedwith K₂CO₃ (500 mg). The reaction was heated at 45° C. for 40 min beforeit was cooled down to room temperature. The crude mixture was dilutedwith aqueous NH₄Cl and extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄. The solventwas removed and the mixture was purified by flash column chromatography(EtOAc in hexanes, 10-40% gradient) to give the desired product (200mg). ¹H NMR (CDCl₃) δ: 1.23 (t, J=12.07 Hz, 3H) 1.60-1.83(m, 11H),2.00-2.38 (m, 3H), 2.60 (m, 2H), 2.82-3.20 (m, 6H), 3.35 (m, 2H), 3.90(m, 2H), 6.66(m, 2H), 6.99 (s, 1H).

Step 2: Preparation of Compound{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)but-1-ynyl]-2-ethylphenoxy}acetonitrile

To a solution (4-bromo-2-ethylphenoxy)acetonitrile (1.99 g, 8.33 mmol)in diisopropylamine (9 mL) and DMF (3 mL) was added6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(2.00 g, 7.57 mmol), PdCl₂(PPh₃)₂ (211 mg, 4 mol %), CuI (115 mg, 8 mol%). The mixture was heated to 90° C. for 30 min before it was cooleddown to room temperature. The reaction was diluted with aqueous NH₄Cl,extracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine, dried with Na₂SO₄ and evaporated to dryness. Themixture was purified by flash column chromatography (10-50% EtOAc inhexanes) to give the product (1.9 g). ¹H NMR (300 MHz, CDCl₃) δ: 1.23(t, J=12.07 Hz, 3H) 1.35-1.80 (m, 14H), 2.30 (m, 1H), 3.50 (m, 5H), 4.62(s, 2H), 4.87 (s, 1H), 6.90 (d, J=2.54 Hz, 1H), 7.14 (m, 1H), 7.38 (m,1H).

Step 1: Preparation of Compound (4-bromo-2-ethylphenoxy)acetonitrile

Bromoacetonitrile (1.19 ml, 9.94 mmol) was added to a solution of4-bromo-2-ethylphenol (2.0 g, 9.94 mmol) and potassium carbonate (1.35g, 9.94 mmol) in DMF (50 ml). The reaction was stirred for 12 hours andthen partitioned between diethyl ether (200 ml) and water (200 ml). Theorganics were separated, dried over magnesium sulfate, filtered andconcentrated in vacuuo to afford the title compound as a yellow oil (2.0g). ¹H NMR (CDCl₃): δ 1.13 (t, J=12.07 Hz, 3H), 2.45 (m, 2H), 4.84 (s,2H), 7.03-7.10 (m, 2H), 7.21 (m, 1H).

Example A(140)2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-1,2,4)triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl]-2,6-difluoro-phenyl]-2-methyl-propionitrile

A solution of2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile(389 mg, 1.0 mmol) in anhydrous MeOH (4.0 mL) was treated with5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (76.6 mg,1.30 mmol), followed by borane-dimethylamine complex at roomtemperature. The reaction was stirred for 12 hours before it wasquenched by the addition of 1 N HCl. The mixture was extracted with 10%MeOH in CH₂Cl₂ (3×10 mL) and the combined organic layers were washedwith brine, dried over MgSO₄. The solvent was removed and the residuewas purified by flash column chromatography (80% EtOAc, 14% Hexane, 6%MeOH and 0.5% Acitic acid) to give the product (192 mg, 35% yield). ¹HNMR (CDCl₃) δ: 1.52-1.75 (m, 6H), 1.83 (s, 3H), 1.93-1.99 (m, 3H), 2.09(s, 3H), 2.36 (m, 1H), 2.45 (d, J=17.94 Hz, 2H), 2.60-2.64 (m, 2H), 2.66(s, 3H), 2.72 (d, J=6.06 Hz, 1H), 2.78 (d, J=7.33 Hz, 1H), 2.79 (s, 3H),4.08 (s, 2H), 6.68 (d, J=10.86 Hz, 2H), 6.85 (s, 1H). MS (ESI): 548(M−H).

Example A(141)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to step 4 in Example A(97),substituting2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluoro-phenyl}-2-methyl-propionitrilein place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (CDCl₃) δ: 1.38-1.48 (m, 4H), 1.57-1.77 (m, 5H), 1.85 (s, 6H),1.92 (t, J=8.59 Hz, 2H), 2.25 (m, 1H), 2.65 (dd, J=15.92, 7.58 Hz, 2H),2.75 (dd, J=28.80, 15.66 Hz, 2H), 3.43 (d, J=4.55 Hz, 2H), 6.71 (d,J=10.86 Hz, 1H). MS (ESI): 388 (M−H).

Step 4: Preparation of Compound2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to step 3 in Example A(97),substituting 2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile inplace of 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile. ¹H NMR(CDCl₃) δ: 1.38-1.48 (m, 4H), 1.57-1.77 (m, 5H), 1.85 (s, 6H), 1.92 (t,J=8.6 Hz, 2H), 2.25 (m, 1H), 2.65 (dd, J=15.9, 7.6 Hz, 2H), 2.75 (dd,J=28.8, 15.7 Hz, 2H), 3.43 (d, J=4.6 Hz, 2H), 6.71 (d, J=10.9 Hz, 1H).MS (ESI): 442 (M−H).

Step 3: Preparation of Compound2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to step 2 in Example A(97),substituting (4-Bromo-2,6-difluoro-phenyl)-acetonitrile in place of1-(4-bromo-2-fluoro-phenyl)-acetonitrile. ¹H NMR (CDCl₃) δ: 1.87 (s,6H), 7.13 (d, J=9.3 Hz, 2H).

Step 2: Preparation of Compound(4-Bromo-2,6-difluoro-phenyl)-acetonitrile

The desired product was prepared analogously to step 1 in Example A(97),substituting (4-Bromo-2,6-difluoro-phenyl)-acetonitrile from step 1below in place of 1-(4-bromo-2-fluoro-phenyl)-c acetonitrile. ¹H NMR(CDCl₃) δ: 3.59 (s, 2H), 7.18 (d, J=6.6 Hz, 2H).

Step 1: Preparation of Compound5-Bromo-2-bromomethyl-1,3-difluoro-benzene

A solution of 5-Bromo-2-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at roomtemperature for 90 minutes before it was poured into 80 ml of water. Themixture was extracted with pentane (3×50 ml) and the combined organiclayers were washed with water (3×20 ml), dried over MgSO₄ andconcentrated at low pressure to afford the desired product (10.0 g, 98%yield). ¹H NMR (CDCl₃) δ: 4.47 (s, 2H), 7.09-7.10 (m, 1H), 7.12-7.13 (m,1H).

Example A (142)2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to Example A (140),substituting 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde inplace of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (CDCl₃) δ: 1.57-1.71 (m, 4H), 1.83 (s, 6H), 1.94-2.00 (m, 3H),2.33-2.40 (m, 2H), 2.46 (d, J=17.68 Hz, 1H), 2.65 (t, J=9.09 Hz, 2H),2.75 (d, J=18.19 Hz, 2H), 3.42 (d, J=2.02 Hz, 1H), 3.75 (t, J=9.35 Hz,1H), 4.11 (s, 2H), 6.68 (d, J=10.86 Hz, 2H), 8.78 (d, J=2.53 Hz, 1H),8.87 (d, J=2.53 Hz, 1H). MS (ESI): 555 (M−H).

Example A (143)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to Example A (140),substituting 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde inplace of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (CDCl₃) δ: 1.34-1.40 (m, 2H), 1.60-1.73 (m, 4H), 1.83 (s, 6H),1.83-1.86 (m, 3H), 1.93-1.99 (m, 2H), 2.37 (m, 1H), 2.42 (d, J=5.56 Hz,1H), 2.48 (s, 3H), 2.64 (t, J=8.34 Hz, 2H), 2.75 (d, J=17.94 Hz, 1H),4.09 (s, 2H), 6.67 (d, J=11.12 Hz, 2H), 8.61 (d, J=1.26 Hz, 1H), 8.69(d, J=2.27 Hz, 1H). MS (ESI): 534 (M−H).

Example A (144)2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to Example A (140),substituting [1,2,4]Triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(CDCl₃) δ: 1.11 (t, J=7.1 Hz, 2H), 1.49-1.61 (m, 6H), 1.84 (s, 6H),1.86-1.88 (m, 1H), 1.95-1.99 (m, 1H), 2.40-2.26 (m, 1H), 2.49 (d,J=17.94 Hz, 1H), 2.66 (t, J=8.85 Hz, 2H), 2.77 (d, J=17.69 Hz, 1H), 4.13(s, 2H), 6.89 (d, J=10.87 Hz, 2H), 7.20 (t, J=6.06 Hz, 1H), 8.85-8.87(m, 2H). MS (ESI): 520 (M−H).

Example A(145)2-{4-[2-(2-Cyclopentyl-4-methoxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile

A magnetically stirring solution of2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile(− rotation, 0.15 g, 0.40 mmol) was cooled to 0° C. DBU (0.18 mL, 1.21mmol) was added followed by Mel (0.076 mL, 1.21 mmol) and reaction wasstirred at 0° C. for 1 hour. The reaction mixture was partitionedbetween 1N HCl and EtOAc. The layers of the resulting reaction mixturewere separated and the organic layer was washed with brine (1×10 mL),then dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by flash column chromatography (20% EtOAc inHexanes) to give the desired product as a yellow oil (0.062 g, 41%). ¹HNMR (400 MHz, CDCl₃): δ 1.18 (d, J=6.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H),1.50-1.78 (m, 8H), 1.94-2.05 (m, 2H), 2.18 (s, 3H), 2.64-2.73 (m, 3H),3.75 (s, 2H), 5.17 (s, 1H), 6.89-6.97 (m, 2H), 7.35-7.40 (m, 1H). MS(ESI): 386 (M+H).

Example A(146)2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example B(97), where2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrilewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.39-1.64 (m, 8H), 1.67(s, 6H), 2.01-2.05 (m, 2H), 2.36-2.46 (m, 7H), 2.51-2.57 (m, 2H),2.69(d, J=17 Hz, 2H), 3.61(d, J=16 Hz, 1H), 3.72 (d, J=16 Hz, 1H), 6.94(s, 1H), 7.25 (s, 1H), 7.28 (s, 1H), 7.35 (d, J=8 Hz, 1H), 10.75 (s,1H). IR (neat): 2243, 2355 (CN), 1666, 1625, 1543, 1390. Anal. Calcd.For C₃₀H₃₄ClN₅O₃.1.0H₂O: C, 63.65; H, 6.41; N, 12.37. Found: C, 63.60;H, 6.30; N, 12.21. MS(ESI): 549 (M+H)⁺.

Example A(147)2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile

The title compound was prepared analogously to step 4 from ExampleA(97), where 2-(4-Bromo-2-chloro-phenyl)-2-methyl-propionitrile(described in step 4 below) was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. ¹H NMR (400 MHz, CDCl₃): δ 1.39-1.71 (m, 8H), 1.81-1.87 (m,8H), 2.10-2.15 (m, 1H), 2.59-2.68 (m, 2H), 3.51 (s, 2H), 3.75 (s, 2H),7.11 (dd, J=8.1 Hz, 1.8), 7.27 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.1 Hz,1H). MS (ESI): 388 (M+H)⁺.

Step 4: 2-(4-Bromo-2-chloro-phenyl)-2-methyl-propionitrile

NaH (95%, 1.18 g, 49.35 mmol) was suspended in DMF (25 mL) and cooled to0° C. 4-Bromo-2-chloro-phenyl)-acetonitrile (2.27 g, 9.87 mmol) fromstep 3 below, was dissolved in THF (10 mL) and slowly added via cannulaand the reaction mixture stirred 20 min. Mel (6.10 mL, 98 mmol) wasadded and the resulting mixture was stirred overnight at roomtemperature. Reaction was quenched with H₂O (50 mL). Solvents wereremoved in vacuo and residue partitioned between EtOAc and 1N HCl (50mL). The organic phase was dried over Na₂SO₄ and evaporated. The crudeorganic product was purified by flash column chromatography (5% EtOAc inhexanes) to give the product (2.23 g, 87%) as a clear oil. ¹H NMR (400MHz, CDCl₃): δ 7.34 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H),7.61 (d, J=1.8 Hz, 1H).

Step 3: (4-Bromo-2-chloro-phenyl)-acetonitrile

To a magnetically stirring solution of4-Bromo-1-bromomethyl-2-chloro-benzene (3.59 g, 12.67 mmol) from step 2below and tetrabutylammonium bromide (0.41 g, 1.27 mmol) in CH₂Cl₂/H₂O1:1 (60.0 mL), was added a solution of KCN (2.48 g, 38.01 mmol) in H₂O(30 mL). The resulting orange mixture was stirred at room temperaturefor 3 hours. The layers of the resulting reaction mixture were separatedand the organic layer was washed with NaHCO₃ sat solution (3×50 mL),then dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by flash chromatography (30% EtOAc in Hexanes) toyield the intermediate as a clear oil (3.59 g, 100%). ¹H NMR (400 MHz,CDCl₃): δ 3.79 (s, 2H), 7.37-7.60 (m, 3H).

Step 2: 4-Bromo-1-bromomethyl-2-chloro-benzene

To a magnetically stirring solution of 4-Bromo-2-chloro-phenyl)-methanol(2.80 g, 12.67 mmol) from step 1 below in CH₂Cl₂ (60.0 mL) under argonat 0° C., was added carbon tetrabromide (4.41 g, 13.30 mmol) followed bytriphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture wasstirred for 4 hours at room temperature. The resulting reaction mixturewas concentrated in vacuo and the crude residue was purified by flashcolumn chromatography (10% EtOAc in Hexanes) to yield the intermediatebromide as a clear oil (3.59 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ 4.53(s, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.39 (dd, J=8.2, 1.9 Hz, 1H), 7.56 (d,J=1.9 Hz, 1H).

Step 1: (4-Bromo-2-chloro-phenyl)-methanol

4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF(100 mL) and cooled to 0° C. A 1M solution of BH₃.THF in THF (31.85 mL,31.85 mmol) was slowly added. The reaction was stirred overnight,allowing it to gradually reach room temperature. K₂CO₃ solid (1 g) andH₂O (100 mL) were added and the reaction was stirred for 30 minutes. THFwas evaporated and residue extracted with EtOAc (30 mL). The organicphase was washed with 1N HCl (3×50 mL), brine (3×50 mL), dried overNa₂SO₄ and evaporated. The residue was purified by flash columnchromatography (30% EtOAc in hexanes) to give the product (2.80 g, 50%)as a color less oil. ¹H NMR (400 MHz, CDCl₃): δ 4.73 (d, J=5.8 Hz, 2H),7.37 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1 Hz, 1.7), 7.52 (d, J=1.7 Hz,1H).

Example A(148)1-(2-Chloro-{42-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile

The title compound was prepared analogously to Example B(97), where1-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-cyclopropanecarbonitrile(from step 2 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.50-1.53 (m, 4H),1.65-1.75 (m, 8H), 1.87-1.99 (m, 2H), 2.26-2.29 (m, 1H), 2.62 (s, 3H),2.72 (s, 3H), 2.62-2.78 (m, 3H), 2.95 (d, J=17 Hz, 1H), 3.87(d, J=16 Hz,1H), 3.98 (d, J=16 Hz, 1H), 7.20(s, 1H), 7.45 (dd, J=7.8, 1.3 Hz, 1H),7.55-7.59 (m, 2H), 11 (brs, 1H). Anal. Calcd. For C₃₀H₃₂ClN₅O₃.0.4H₂O:C, 65.13; H, 5.98; N, 12.66. Found: C, 65.52; H, 6.02; N, 12.29.MS(ESI): 547(M+H)⁺.

Example A(149)1-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]phenyl}-cyclopropanecarbonitrile

The title compound was prepared analogously to step 4 from ExampleA(97), where 1-(4-Bromo-2-chloro-phenyl)-cyclopropanecarbonitrile (fromstep 1 below) was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. ¹H NMR (400 MHz, CDCl₃): δ 1.26-1.33 (m, 4H), 1.53-1.75 (m,8H), 1.90-1.95 (m, 2H), 2.24-2.29 (m, 1H), 2.64-2.69 (m, 2H), 2.77 (d,J=6.5 Hz, 2H), 3.43 (d, J=3.5 Hz, 2H), 7.03 (dd, J=7.8, 1.7 Hz, 1H),7.23 (d, J=1.7 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H). IR (neat): 3084, 2931(CN), 1584, 1561, 1466. Anal. Calcd. For C₂₂H₂₄ClNO₃.0.25H₂O: C, 67.69;H, 6.33; N, 3.59. Found: C, 67.55; H, 6.34; N, 3.58.

MS(ESI): 384(M+H)⁺.

Step 1: 2-(4-Bromo-2-chloro-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to step 4 from ExampleA(147), where 1-Bromo-2-chloroethane was substituted in place of methyliodide of that example. ¹H NMR (400 MHz, CDCl₃): δ 7.22 (d, J=8.2 Hz,1H), 7.39 (dd, J=8.2 Hz, 1.9, 1H), 7.61 (d, J=1.9 Hz, 1H).

Example A(150)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(from step 2 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.01 (t, J=7.4 Hz, 3H),1.41-1.76 (m, 8H), 1.87-2.12 (m, 2H), 2.37-2.53 (m, 11H), 2.58 (d, J=17Hz, 1H), 2.73 (d, J=17 Hz, 1H), 3.59 (s, 3H), 3.70 (d, J=17 Hz, 1H),3.80 (d, J=17 Hz, 1H), 6.34 (s, 1H), 6.73 (s, 1H), 7.0 (s, 1H), 9.0 (s,1H), 10.62 (s, 1H). Anal. Calcd. For C₂₉H₃₆N₄O₅.0.5CH₂Cl₂ 0.5H₂O: C,61.93; H, 6.69; N, 9.79. Found: C, 62.02; H, 7.08; N, 9.48. MS(ESI): 521(M+H)⁺.

Example A(151)6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from ExampleA(97), where 4-bromo-2-ethyl-5-methoxyphenyl acetate (described in step1 below) was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. ¹H NMR (400 MHz, CDCl₃): δ 1.19 (t, J=7.4 Hz, 3H) 1.53-1.54 (m,8H), 1.81-1.95 (m, 2H), 2.31-2.36 (m, 1H), 2.52 (q, J=7.4 Hz, 2H),2.59-2.65 (m, 2H), 2.75 (d, J=7.3 Hz, 2H), 3.41 (s, 2H), 3.74 (s, 3H),4.71 (s, 1H), 6.35 (s, 1H), 6.80 (s, 1H). Anal. Calcd. ForC₂₁H₂₈O₅.0.25H₂O: C, 69.11, H, 7.87. Found: C, 69.13, H, 8.00. MS(ESI):359 (M+H)⁺.

Step 1: Preparation of Compound 4-bromo-2-ethyl-5-methoxyphenyl Acetate

The title compound was prepared analogously to step 4 from ExampleA(124), where 2′-hydroxy-4′-methoxy acetophenone was substituted inplace of 2-fluoro-6-(1-hydroxy-ethyl)-phenol in step 2 of that example.¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, J=7.4 Hz, 3H), 2.32 (s, 3H), 2.45(q, J=7.4 Hz, 2H), 3.85 (s, 3H), 6.59 (s, 1H), 7.42 (s, 1H).

Example A(152)(+)-2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example B(97), where(+)-2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2yl)ethyl]2-fluorophenyl}-2-methylpropanenitrilewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.25-1.57 (m, 8H), 1.72(s, 6H), 2.11-2.17 (m, 2H), 2.50-2.56 (m, 8H), 2.63-2.65 (m, 2H),2.78(d, J=16 Hz, 1H), 3.71(d, J=16 Hz, 1H), 3.84 (d, J=16 Hz, 1H), 7.06(s, 1H), 7.17-7.23 (m, 2H), 7.36-7.42 (m, 1H), 10.88 (s, 1H). Anal.Calcd. For C₃₀H₃₆FN₅O₃.1.0H₂O: C, 65.56; H, 6.60; N, 12.74. Found: C,65.50; H, 6.41; N, 12.61. MS(ESI): 532 (M+H)⁺.

Step 4:(+)-2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile

The title compound was prepared analogously to from Example A(97), where(+)-6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas substituted in place of the racemic material. ¹H NMR (CDCl₃) δ:1.60-1.73(m, 6H), 1.92-1.98 (m, 2H), 2.22-2.30 (m, 1H), 2.65-2.71 (m,2H), 2.75-2.80 (m, 2H), 6.88-6.96 (m, 2H), 7.37-7.43 (m, 1H). MS(ESI):372 (M+H)⁺.

Step 3: Preparation of Compound(+)-6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one

To the optically pure(+)-1-cyclopentyl-1-[(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl]prop-2-ynylethyl oxalate (2.5 g, 15.1 mmol) in 50 ml of MeOH was added K₂CO₃ (2.0g). The mixture was stirred at 23° C. for 8 h. After completeconversion, the mixture was neutralized with 1N HCl at cold temperature.The aqueous solution was extracted with MTBE (×3) and the organic layerwas washed with brine and dry over MgSO₄. After removal of MTBE, 1.75 gof the desired product (+enantiomer) was produced with 95.5% ee and 96%yield.

Step 2: Preparation of Compound(−)-6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one

To a 250 ml three-necked flask equipped with a pH electrode was added 72ml of phosphate buffer (pH 4.0, 0.5M) and Candida rugosa lipase (5 g,Amano AY). The mixture was stirred vigorously and then the racemicoxalate (from step 1 below, 6 g) in 18 ml of acetonitrile was added. Thereaction mixture was allowed to stir at 23° C. and the pH was kept at4.0 using a pH titrator. The reaction was monitored with HPLC andstopped after 50% conversion (<20 hrs). The mixture was extracted byMTBE (×3) and the combined organic layer was dried over MgSO₄. Afterremoval of the solvent, the crude product was separated carefully bysilica-gel chromatography, using heptane/EtOAC, which afforded 2.6 g ofthe oxalate (+enantiomer, 43% yield, 96% ee) and 2.0 g of product (−enantiomer, 46% yield, 92% ee). ¹H NMR (300 MHz, CDCl₃): δ 1.45-1.80 (m,8H), 1.72 (s, 3H), 1.74 (s, 3H), 2.13-2.18 (m, 1H), 2.49 (s, 1H), 2.56(s, 1H), 2.58 (s, 2H), 5.43 (s, 1H).

Step 1: Preparation of Compound1-cyclopentyl-1-[(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl]prop-2-ynylEthyl Oxalate

To a solution of racemic6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(10 g, 37.9 mmol) in CH₂Cl₂ (200 ml) was added triethylamine (3.0 eq,113.7 mmol) at 0° C. Then ethyl chlorooxoacetate (3.0 eq, 113.7 mmol) inCH₂Cl₂ (10 ml) was added dropwise over a 30-minute period under argon.The solution was allowed to stir overnight at room temperature. Afterremoval of solvent, the crude product was purified using a flash column(heptane: EtOAc, 3:1) to afford the desired oxalate (13.5 g, >95%).API-MS: [M+Na⁺]: 387;

Example A(153) Preparation of Compound(−)-2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example B(97), where(−)-2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2yl)ethyl]2-fluorophenyl}-2-methylpropanenitrile(from step 1 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.25-1.57 (m, 8H), 1.72(s, 6H), 2.11-2.17 (m, 2H), 2.50-2.56 (m, 8H), 2.63-2.65 (m, 2H),2.78(d, J=16 Hz, 1H), 3.71(d, J=16 Hz, 1H), 3.84 (d, J=16 Hz, 1H), 7.06(s, 1H), 7.17-7.23 (m, 2H), 7.36-7.42 (m, 1H), 10.88 (s, 1H). Anal.Calcd. For C₃₀H₃₄FN₅O₃.0.3 EtOAc: C, 65.15; H, 6.57; N, 12.55. Found: C,66.86; H, 6.59; N, 12.21. MS(ESI): 532 (M+H)⁺.

Step 1: Preparation of Compound(−)-2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile

The title compound was prepared analogously to from Example A(97), where(−)-6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas substituted in place of the racemic material. ¹H NMR (400 MHz,CDCl₃): δ 1.60-1.73(m, 6H), 1.92-1.98 (m, 2H), 2.22-2.30 (m, 1H),2.65-2.71 (m, 2H), 2.75-2.80 (m, 2H), 6.88-6.96 (m, 2H), 7.37-7.43 (m,1H).

Example A(154)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared via chiral separation of Example A(150),6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one.The method used involved a Chiralpak AS-RH, 150×4.6 mm column, 0.6mL/min, 50% CAN; 50% H₂O, 30 min. ¹H NMR (400 MHz, DMSO-d₆): δ 1.01 (t,J=7.4 Hz, 3H), 1.41-1.76 (m, 8H), 1.87-2.12 (m, 2H), 2.37-2.53 (m, 11H),2.58 (d, J=17 Hz, 1H), 2.73 (d, J=17 Hz, 1H), 3.59 (s, 3H), 3.70 (d,J=17 Hz, 1H), 3.80 (d, J=17 Hz, 1H), 6.34 (s, 1H), 6.73 (s, 1H), 7.0 (s,1H), 9.0 (s, 1H), 10.62 (s, 1H). MS(ESI): 521 (M+H)⁺. Retention timeusing the conditions above was 8.64 min. 100% ee, (+) rotation.

Example A(155) Preparation of Compound(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared via chiral separation of Example A(150),6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one.The method used involved a Chiralpak AS-RH, 150×4.6 mm column, 0.6mL/min, 50% CAN; 50% H₂O, 30 min. ¹H NMR (400 MHz, DMSO-d₆): δ 1.01 (t,J=7.4 Hz, 3H), 1.41-1.76 (m, 8H), 1.87-2.12 (m, 2H), 2.37-2.53 (m, 11H),2.58 (d, J=17 Hz, 1H), 2.73 (d, J=17 Hz, 1H), 3.59 (s, 3H), 3.70 (d,J=17 Hz, 1H), 3.80 (d, J=17 Hz, 1H), 6.34 (s, 1H), 6.73 (s, 1H), 7.0 (s,1H), 9.0 (s, 1H), 10.62 (s, 1H). MS(ESI): 521 (M+H)⁺. Retention timeusing the conditions above was 6.13 min. 100% ee, (−) rotation.

Example A(156)6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-3-(5-methyl-1H-imidazol-4-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126), where6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas substituted in place of6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dioneand 4-methyl-5-imidazol carboxaldehyde was substituted in place of6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample. ¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (t, J=7.5 Hz, 3H), 1.10-1.56(m, 10H), 1.73-1.68 (m, 1H), 1.92 (s, 3H), 2.21-2.5 (m, 6H), 3.20-3.22(m, 2H), 3.44 (s, 3H), 6.17 (s, 1H), 6.50 (s, 1H), 7.53 (s, 1H). Anal.Calcd. For C₂₆H₃₄N₂O₅.1H₂O: C, 66.08; H, 7.68; N, 5.93. Found: C, 65.93;H, 7.66; N, 5.89. MS(ESI): 455.2 (M+H)⁺.

Example A(157)6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-3-(2-ethyl5-methyl-1H-imidazol-4-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126), where6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas substituted in place of6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dioneand 2-ethyl-5-formyl-4-methylimidazole was substituted in place of6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample. ¹H NMR (400 MHz, DMSO-d₆): δ 1.07-1.34 (m, 6H), 1.49-1.81 (m,10H), 2.13 (s, 3H), 2.28-2.35 (m, 1H), 2.39-2.68 (m, 8H), 3.40 (d, J=6.9Hz, 2H), 3.68 (s, 3H), 6.41 (s, 1H), 6.74 (s, 1H). Anal. Calcd. ForC₂₈H₃₈N₂O₅.1H₂O: C, 67.18; H, 8.05; N, 5.60. Found: C, 67.50; H, 8.09;N, 5.60. MS(ESI): 483.2 (M+H)⁺.

Example A(158)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(150), where6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (300 MHz, DMSO-d₆) δ: 1.02 (t, J=7.44 Hz, 3H), 1.30-1.69 (m, 8H),1.85-1.92 (m, 2H), 2.25-2.44 (m, 7H), 3.62 (s, 3H), 3.71 (s, 2H), 6.36(s, 1H), 6.72 (s, 1H), 8.81 (d, J=2.64 Hz, 1H), 9.47 (d, J=2.45 Hz, 1H).Anal. Calcd. For C₂₇H₃₁ClN_(405.0.5)H₂O: C, 60.50; H, 6.02; N, 10.45.Found: C, 60.43; H, 6.22; N, 10.20.

Example A(159)6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(150), where6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (300 MHz, DMSO-d₆) δ: 0.95 (t, J=7.44 Hz, 3H), 1.30-1.64 (m, 8H),1.84-1.92 (m, 2H), 2.27-2.38 (m, 7H), 3.55 (s, 3H), 3.68-3.70 (m, 2H),6.30 (s, 1H), 6.68 (s, 1H), 8.61 (d, J=3.0 Hz, 1H), 8.74 (s, 1H), 8.95(s, 1H).

HRMS calcd for C₂₈H₃₅N₄O₅ (M+H)⁺: 507.2602, found 507.2616.

Example A(160)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.16 g, 0.85mmol) was added to a solution of6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(0.2 g, 0.53 mmol, from step 1 below) in MeOH (7 mL). The reactionmixture was stirred for 20 mins and then treated withborane-dimethylamine complex (63 mg, 1.1 mmoL). After 15 hours thereaction mixture was quenched with conc HCl and concentrated to a brownoil. Purification by flash silica gel chromatography (50% EtOAc inhexanes then 0% to 5% MeOH in CH₂Cl₂) gave the product as a white solid(50 mg, 14%). ¹H NMR (400 MHz, DMSO-d₆) δ: 1.06 (t, J=7.6 Hz, 3H),1.36-1.68 (br m, 8H), 1.88 (m, 2H), 2.04 (m, 3H), 2.43-2.56 (m, 4H),2.75 (d, J=16.9 Hz, 1H), 3.29-3.44 (m, 2H), 4.64 (s, 2H), 6.51 (s, 1H),6.72 (m, 2H), 8.84 (s, 1H), 9.59 (d, J=4.0 Hz, 1H), 10.77 (s, 1H). MS(ESI): 513.30 (M+H⁺).

Step 1:6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where1-(2-hydroxy-4-methyl-phenyl)-ethanone was substituted in place of2-fluoro-6-(1-hydroxy-ethyl)-phenol in step 2 of that example. ¹H NMR(400 MHz, CDCl₃): δ 1.20 (t, J=7.6 Hz, 3H), 1.55-1.94 (br m, 10H), 2.19(s, 3H), 2.32 (m, 1H), 2.58 (m, 4H), 2.79 (s, 2H), 3.42 (s, 2H), 4.53(s, 1H), 6.56 (s, 1H), 6.81 (s, 1H).

Example A(161)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-fluoro-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(160) where1-(4-fluoro-2-hydroxy-phenyl)-ethanone was substituted in place of1-(2-hydroxy-4-methyl-phenyl)-ethanone in step 1 of that example. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.00 (t, J=7.6 Hz, 3H), 1.24-1.58 (br m, 8H), 1.90(m, 2H), 2.29-2.49 (m, 4H), 2.64 (d, J=17.2 Hz, 1H), 3.32-3.37 (m, 2H),4.58 (s, 2H), 6.43 (d, J=11.7 Hz, 1H), 6.61 (d, J=5.1 Hz, 1H), 6.80 (d,J=9.4 Hz, 1H), 9.43 (s, 1H), 9.53 (d, J=5.1 Hz, 1H), 10.7 (s, 1H).

Example A(162)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-cyclopentyl-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-dihydro-pyran-2,4-dione(Example A(163) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.24 (t, J=7.6 Hz, 3H), 1.44-1.75 (br m,8H), 2.2 (m, 2H), 2.50-2.86 (m, 13H), 3.76 (d, J=16.0 Hz, 1H), 3.89 (d,J=16.0 Hz, 1H), 7.11 (s, 1H), 7.18 (s, 2H), 8.39 (s, 1H), 11.12 (s, 1H).MS (ESI): 476.25 (M+H⁺).

Example A(163)6-Cyclopentyl-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(97) where4-bromo-2-ethyl-pyridine (from step 3 below) was substituted in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile in step 3 of thatexample. ¹H NMR (400 MHz, CDCl₃): δ 1.30 (t, J=7.6 Hz, 3H), 1.37-1.76(br m, 8H), 1.96 (m, 2H), 2.28 (s, 1H), 2.68 (m, 2H), 2.79 (m, 4H), 3.44(s, 2H), 6.91 (s, 1H), 6.95 (s, 1H), 8.42 (s, 1H). Anal. Calcd. ForC₁₉H₂₅NO₃.0.5H₂O: C, 70.34; H, 8.08; N, 4.32. Found: C, 70.37; H, 7.96;N, 4.34.

Step 3: 4-Bromo-2-ethyl-pyridine

A mixture of 2-ethyl-4-nitro-pyridine (2.3 g, 15.1 mmol) and acetylbromide (9 mL) were heated together at 75° C. for 16 hours. More acetylbromide (10 mL) was added and the reaction was heated to 100° C. for 5hrs. The reaction mixture was poured into ice, made basic with 20% NaOHand extracted with EtOAc. The organic extracts were washed with brine,dried over Na₂SO₄ and concentrated to a black oil. Purification by flashsilica gel chromatography (0% to 25% EtOAc) gave the product as an oil(1.72 g, 62%). ¹H NMR (400 MHz, CDCl₃): δ 1.30 (t, J=7.6 Hz, 3H), 2.81(d, J=7.6 Hz, 2H), 7.28 (dd, J=5.3, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H),8.34 (d, J=5.3 Hz, 1H).

Step 2: 2-Ethyl-4-nitro-pyridine

A solution of phosphorous trichloride (7.2 mL, 82 mmol) in CH₂Cl₂ wasadded to a cooled 0° C. solution of 2-ethyl-4-nitro-pyridine 1-oxide (3g, 17.8 mmol) in CH₂Cl₂. The reaction was stirred for 2 hours and thenwarmed up to rt. After 3 hours the mixture was poured into ice, madebasic with 15% NaOH and extracted with EtOAc. The organic extracts weredried over Na₂SO₄ and concentrated to a yellow oil that solidified onstanding (2.56 g, 95%). ¹H NMR (400 MHz, CDCl₃): δ 1.40 (t, J=7.6 Hz,3H), 3.14 (d, J=7.6 Hz, 2H), 8.04 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 8.92(d, J=5.6 Hz, 1H).

Step 1: 2-Ethyl-4-nitro-pyridine 1-oxide

Hydrogen peroxide (4.8 mL, 47 mmol, 30% wt in H₂O) was added to asolution of 2-ethylpyridine (5 g, 47 mmol) in AcOH (30 mL). The reactionwas refluxed for 24 hours and then concentrated to a dark oil.

The oil was dissolved in H₂SO₄ (11.4 mL) and cooled to 0° C. HNO₃ (9.2mL) was added slowly and after the addition was complete the reactionmixture was heated to 100° C. for 16 hours. The mixture was poured intoice, made basic with 15% NaOH and extracted with CH₂Cl₂. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated.Purification by by flash column chromatography (40% to 60% EtOAc inhexanes) gave the title compound as a yellow solid (3.13 g, 53%). ¹H NMR(400 MHz, CDCl₃): δ 1.37 (t, J=7.3 Hz, 3H), 2.96 (d, J=7.3 Hz, 2H), 7.99(dd, J=7.1, 3.1 Hz, 1H), 8.10 (d, J=3.1 Hz, 1H), 8.31 (d, J=7.1 Hz, 1H).

Example A(164)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(160) where6-cyclopentyl-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-dihydro-pyran-2,4-dione(Example A(163)) was substituted in place of6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.18 (t, J=6.1 Hz, 3H), 1.34-1.66 (br m,8H), 1.99 (m, 1H), 2.12 (m, 1H), 2.33 (m, 2H), 2.50-2.62 (m, 3H), 2.70(d, J=6.1 Hz, 2H), 3.69 (d, J=16.0 Hz, 1H), 3.80 (d, J=16.0 Hz, 1H),5.77 (s, 1H), 7.10 (m, 2H), 8.33 (d, J=4.8, 1H), 8.86 (d, J=2.5, 1H),9.53 (d, J=6.1 Hz, 1H).

Example A(165)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(2-ethyl-pyridin-4-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(160) where1-(2-hydroxy-4-trifluoromethyl-phenyl)-ethanone (from step 1 below) wassubstituted in place of 1-(2-hydroxy-4-methyl-phenyl)-ethanone in step 1of that example. ¹H NMR (400 MHz, DMSO-d₆) δ: 1.07 (t, J=7.3 Hz, 3H),1.34-1.66 (br m, 8H), 1.91-2.11 (m, 2H), 2.37-2.70 (m, 7H), 3.75 (s,2H), 5.77 (s, 1H), 7.00 (s, 1H), 7.07 (s, 1H), 8.84 (s, 1H), 9.52 (s,1H), 9.75 (s, 1H).

Step 1: 1-(2-Hydroxy-4-trifluoromethyl-phenyl)-ethanone

4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (5 g, 29.7 mmol) followed by2,4-pentadione (3.05 ml, 29.7 mmol) were added to a cooled 0° C.suspension of NaH (2.38 g, 59.4 mmol) in THF (120 mL). The reactionmixture was refluxed for 4 hrs and then partitioned between 1N HCl andEtOAc. The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a red oil. Purification by flash column chromatography(0% to 10% EtOAc in hexanes) gave the title compound as a yellow oil(1.73 g, 29%). ¹H NMR (400 MHz, CDCl₃): δ 2.69 (s, 3H), 7.15 (d, J=9.9Hz, 1H), 7.25 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 12.29 (s, 1H).

Example A(166)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g,1.1 mmol) was added to a solution of6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(0.3 g, 0.91 mmol Example A(169)) in MeOH (8 mL). The reaction mixturewas stirred for 15 mins and then treated with borane-dimethylaminecomplex (47 mg, 0.80 mmoL). After 24 hours the reaction mixture wasfiltered through a glass frit to remove a fine white ppt. The filtratewas concentrated and purified by prep HPLC to give the product (175 mg,40%). ¹H NMR (400 MHz, DMSO-d₆) δ: 1.07 (t, J=7.6 Hz, 3H), 1.41-1.72 (brm, 8H), 1.97 (m, 1H), 2.10 (m, 1H), 2.41-2.73 (m, 13H), 3.70 (d, J=16.2Hz, 1H), 3.79 (d, J=16.2 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1Hz, 1H), 6.84 (s, 1H), 7.02 (s, 1H), 9.02 (s, 1H), 10.88 (s, 1H). MS(ESI): 491.20 (M+H⁺).

Example A(167) Enantiomer 1 of6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(118 mg, Example A(166)) using chiral HPLC (Chiralpak AS-H, 120 bar, 2.5mL/min, 30% MeOH). (42.4 mg, 4.695 min retention time).

Example A(168) Enantiomer 2 of6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(118 mg, Example A(166)) using chiral HPLC (Chiralpak AS-H, 120 bar, 2.5mL/min, 30% MeOH). (41.3 mg, 7.341 min retention time).

Example A(169)6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where1-benzyloxy-2-bromo-4-ethyl-benzene (from step 1 of Example D(8) wassubstituted in place of acetic acid 4-bromo-2-ethyl-6-fluoro-phenylester. ¹H NMR (400 MHz, CDCl₃): δ 1.19 (t, J=7.6 Hz, 3H), 1.41-2.07 (brm, 10H), 2.35 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.57-2.82 (br m, 4H),3.45 (d, J=21.2 Hz, 1H), 3.47 (d, J=21.2 Hz, 1H), 4.84 (s, 1H), 6.64 (d,J=7.8 Hz, 1H), 6.91 (m, 2H).). Anal. Calcd. For C₂₀H₂₆O₄.0.2H₂O: C,71.91; H, 7.97. Found: C, 71.96; H, 7.96.

Example A(170)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(166) where6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.09 (t, J=7.6 Hz, 3H), 1.37-1.71 (br m, 8H), 2.01(m, 2H), 2.39-2.54 (m, 5H), 2.61 (d, J=17.7 Hz, 1H), 2.77 (d, J=17.7 Hz,1H), 3.80 (s, 2H), 6.67 (d, J=8.1 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.86(s, 1H), 8.86 (s, 1H), 9.05 (s, 1H), 9.45 (s, 1H), 10.9 (s, 1H). Anal.Calcd. For C₂₆H₂₉N₄O₄Cl_(0.5)H₂O: C, 61.71; H, 5.98; N, 11.07. Found: C,61.73; H, 5.98; N, 10.99.

Example A(171) Enantiomer 1 of3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic3-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(98 mg, Example A(170)) using chiral HPLC (Chiralpak AS-H, 140 bar, 2.5mL/min, 20% MeOH). (26 mg, 12.409 min retention time).

Example A(172) Enantiomer 2 of3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic3-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(98 mg, Example A(170)) using chiral HPLC (Chiralpak AS-H, 140 bar, 2.5mL/min, 20% MeOH). (26 mg, 16.775 min retention time).

Example A(173)6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(166) where6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, DMSO-d₆) δ: 0.99 (t, J=7.6 Hz, 3H), 1.29-1.62 (br m, 8H), 1.92(m, 2H), 2.24 (s, 3H), 2.32-2.50 (m, 6H), 2.63 (d, J=11.6 Hz, 1H), 3.66(s, 2H), 6.58 (d, J=8.1 Hz, 1H), 6.74 (m, 2H), 8.57 (s, 1H), 8.74 (s,1H), 8.95 (s, 1H), 10.85 (s, 1H). MS (ESI): 477.10 (M+H⁺).

Example A(174) Enantiomer 1 of6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one(97 mg, Example A(173)) using chiral HPLC (Chiralpak AS-H, 120 bar, 2.5mL/min, 25% MeOH). (42 mg, 7.534 min retention time).

Example A(175) Enantiomer 2 of6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one(97 mg, Example A(173)) using chiral HPLC (Chiralpak AS-H, 120 bar, 2.5mL/min, 25% MeOH). (37 mg, 10.983 min retention time).

Example A(176)6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-4-hydroxy-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(166) where[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in placeof 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.21 (t, J=7.6 Hz, 3H), 1.50-1.82 (br m, 8H), 2.12(m, 2H), 2.54-2.67 (m, 5H), 2.71 (d, J=17.7 Hz, 1H), 2.87 (d, J=17.7 Hz,1H), 3.90 (s, 2H), 6.79 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.1, 2.0 Hz, 1H),6.98 (s, 1H), 7.37 (dd, J=6.8, 4.3 Hz, 1H), 8.90 (dd, J=4.3, 2.0 Hz,1H), 9.17 (s, 1H), 9.22 (dd, J=6.6, 1.8 Hz, 1H), 11.06 (s, 1H). Anal.Calcd. For C₂₆H₃₀N₄O₄.0.6H₂O: C, 65.97; H, 6.64; N, 11.84. Found: C,66.02; H, 6.53; N, 11.71.

Example A(177)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[5-ethyl-2-(2-methoxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-cyclopentyl-6-{2-[5-ethyl-2-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example A(178)) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.07 (t, J=7.6 Hz, 3H), 1.39-1.73 (br m,8H), 2.05 (m, 1H), 2.40-2.61 (m, 13H), 2.77 (d, J=17.4 Hz, 1H), 3.27 (s,3H), 3.58 (m, 2H), 3.71 (d, J=16.2 Hz, 1H), 3.80 (d, J=16.2 Hz, 1H),3.99 (m, 2H), 6.82 (d, J=8.3 Hz, 1H), 6.91 (dd, J=2.0 Hz, 1H), 6.96 (dd,J=8.3, 2.0 Hz, 1H), 7.02 (s, 1H), 10.8 (s, 1H). Anal. Calcd. ForC₃₁H₄₀N₄O₅.0.3H₂O: C, 67.20; H, 7.39; N, 10.11. Found: C, 67.21; H,7.35; N, 10.11.

Example A(178)6-Cyclopentyl-6-{2-[5-ethyl-2-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where2-bromo-4-ethyl-1-(2-methoxy-ethoxy)-benzene (from step 1 below) wassubstituted in place of acetic acid 4-bromo-2-ethyl-6-fluoro-phenylester. ¹H NMR (400 MHz, CDCl₃): δ 1.19 (t, J=7.6 Hz, 3H), 1.39-2.06 (brm, 10H), 2.35 (m, 1H), 2.59-2.64 (m, 3H), 2.69-2.81 (m, 3H), 3.38 (d,J=21.2 Hz, 1H), 3.41 (s, 3H), 3.58 (d, J=21.2 Hz, 1H), 3.71 (m, 2H),4.08 (m, 2H), 6.74 (d, J=8.3 Hz, 1H), 6.91 (s, 1H), 6.99 (d, J=8.3 Hz,1H). MS (ESI): 387.10 (M−H+).

Step 1: 2-Bromo-4-ethyl-1-(2-methoxyethoxy)-benzene

Potassium carbonate (8.25 g, 60 mol) followed by 2-bromoethyl methylether (1.87 mL, 20 mmol) were added to a solution of2-bromo-4-ethyl-phenol (4 g, 20 mmol, from step 1 of Example B(98)) inDMF (25 mL). The mixture was stirred for 20 hours and then partitionedbetween 1N HCl and EtOAc. The organic layers were washed with brine,dried over Na₂SO₄ and concentrated. The crude yellow oil was purified byflash column chromatography (0% to 10% EtOAc in hexanes) to give thedesired product (4.63 g, 90%). ¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.6Hz, 3H), 2.57 (q, J=7.6 Hz, 2H), 3.48 (s, 3H), 3.79 (t, J=5.1 Hz, 2H),4.15 (t, J=4.8 Hz, 2H), 6.85 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 2.3 Hz,1H), 7.37 (d, J=2.3 Hz, 1H).

Example A(179)6-Cyclopentyl-6-{2-[5-ethyl-2-(2-methoxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126) where6-cyclopentyl-6-{2-[5-ethyl-2-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example A(178)) was substituted in place of6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.24 (t, J=7.6 Hz, 3H), 1.51-1.87 (br m,8H), 2.24 (m, 2H), 2.48 (s, 3H), 2.55 (m, 1H), 2.60-2.73 (m, 5H), 2.90(d, J=18.0 Hz, 1H), 3.43 (s, 3H), 3.75 (t, J=6.1 Hz, 2H), 3.88 (d,J=17.7 Hz, 1H), 3.93 (d, J=17.7 Hz, 1H), 4.16 (d, J=5.1 Hz, 2H), 6.98(d, J=8.3 Hz, 1H), 7.08 (s, 1H), 7.12 (d, J=8.3 Hz, 1H), 8.81 (s, 1H),9.0 (s, 1H), 11.03 (s, 1H). MS (ESI): 535.15 (M+H⁺).

Example A(180)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-dihydro-pyran-2,4-dione(Example A(181)) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.08 (t, J=7.3 Hz, 3H), 1.45-1.75 (br m,8H), 2.01 (m, 1H), 2.15 (m, 1H), 2.39-2.65 (m, 12H), 2.80 (d, J=17.4 Hz,1H), 3.09 (t, J=8.8 Hz, 2H), 3.77 (d, J=15.9 Hz, 1H), 3.85 (d, J=15.9Hz, 1H), 4.47 (t, J=11.4 Hz, 2H), 6.64 (s, 1H), 7.09 (s, 1H), 8.58 (s,1H), 10.89 (s, 1H). Anal. Calcd. For C₃₀H₃₆N₄O₅.0.4H₂O: C, 66.74; H,6.87; N, 10.38. Found: C, 66.71; H, 6.65; N, 10.21.

Example A(181)6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where5-ethyl-2,3-dihydro-benzofuran-4-ol (from step 2 below) was substitutedin place of 2-ethyl-6-fluoro-phenol in step 3 of that example. ¹H NMR(400 MHz, CDCl₃): δ 1.19 (t, J=7.6 Hz, 3H), 1.42-2.05 (br m, 10H), 2.30(m, 1H), 2.47-2.60 (m, 4H), 2.72 (d, J=16.2 Hz, 1H), 2.76 (d, J=16.2 Hz,1H), 3.12 (t, J=8.6 Hz, 2H), 3.43 (m, 2H), 4.56 (t, J=8.6 Hz, 2H), 6.64(s, 1H). MS (ESI): 373.10 (M−H+).

Step 2: 5-Ethyl-2,3-dihydro-benzofuran-4-ol

A mixture of 1-(4-Hydroxy-benzofuran-5-yl)-ethanone (1.37 g, 7.8 mmol)and 10 wt % Pd/C (0.7 g, Degussa type) in MeOH (20 mL) was stirred undera balloon of H₂ for 24 hours. The reaction mixture was filtered througha pad of celite washing with EtOAc. The filtrate was concentrated to anoil (0.9 g, 70%). ¹H NMR (400 MHz, CDCl₃): δ 1.21 (t, J=7.6 Hz, 3H),2.56 (q, J=7.6 Hz, 2H), 3.14 (t, J=8.6 Hz, 2H), 4.59 (t, J=8.6 Hz, 2H),4.68 (s, 1H), 6.37 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H).

Step 1: 1-(4-Hydroxy-benzofuran-5-yl)-ethanone

The title compound was prepared as described in the following reference:Tetrahedron 1995, 51, 4909-4922. ¹H NMR (400 MHz, CDCl₃): δ 1.58 (s,3H), 7.00 (dd, J=2.0, 1.0 Hz, 1H), 7.05 (dd, J=8.8, 1.0 Hz, 1H), 7.57(d, J=2.0 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 13.3 (s, 1H).

Example A(182)6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126) where6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-dihydro-pyran-2,4-dione(Example A(181)) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.09 (t, J=7.3 Hz, 3H), 1.39-1.75 (br m,8H), 2.06 (m, 2H), 2.40-2.62 (m, 9H), 2.80 (d, J=17.7 Hz, 1H), 3.11 (t,J=8.3 Hz, 2H), 3.78 (d, J=15.9 Hz, 1H), 3.84 (d, J=15.9 Hz, 1H), 4.48(t, J=8.6 Hz, 2H), 6.66 (s, 1H), 8.61 (s, 1H), 8.73 (s, 1H), 8.87 (s,1H), 10.97 (s, 1H). MS (ESI): 519.10 (M+H⁺).

Example A(183)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-methoxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-cyclopentyl-6-{2-[3-ethyl-4-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example A(184)) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.13 (t, J=7.6 Hz, 3H), 1.46-1.76 (br m,8H), 2.15 (m, 2H), 2.45-2.64 (m, 12H), 2.85 (d, J=17.4 Hz, 1H), 3.40 (s,3H), 3.71 (t, J=4.6 Hz, 2H), 3.79 (d, J=16.2 Hz, 1H), 3.89 (d, J=16.2Hz, 1H), 4.12 (d, J=4.8 Hz, 2H), 6.89 (d, J=8.3 Hz, 1H), 7.01 (s, 1H),7.06 (dd, J=8.3, 2.3 Hz, 1H), 7.10 (s, 1H), 10.95 (s, 1H). Anal. Calcd.For C₃₁H₄₀N₄O₅.0.75H₂O: C, 66.23; H, 7.44; N, 9.97. Found: C, 66.23; H,7.36; N, 9.81.

Example A(184)6-Cyclopentyl-6-{2-[3-ethyl-4-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(178) where4-bromo-2-ethyl-phenol (from step 1) was substituted in place of2-bromo-4-ethyl-phenol in step 1 of that example. ¹H NMR (400 MHz,CDCl₃): δ 1.18 (t, J=7.3 Hz, 3H), 1.46-1.78 (br m, 8H), 1.89-2.02 (m,2H), 2.27 (s, 1H), 2.62 (m, 4H), 2.76 (s, 2H), 3.42 (s, 2H), 3.45 (s,3H), 3.76 (t, J=4.8 Hz, 2H), 4.09 (t, J=5.0 Hz, 2H), 6.75 (d, J=9.1 Hz,1H), 6.91 (m, 2H). Anal. Calcd. For C₂₃H₃₂O₅: C, 71.11; H, 8.31. Found:C, 71.07; H, 8.27.

Step 1: 4-Bromo-2-ethyl-phenol

A solution of tetrabutyl ammonium tribromide (41.4 g, 86 mmol) in CHCl₃(100 mL) was added to a stirred solution of 2-ethyl phenol (10 g, 81.8mmol) dissolved in CHCl₃ (100 mL). The reaction mixture was stirred for1 hr and then quenched with 5% solution of sodium thiosulfate (100 mL).The biphasic mixture was stirred for 30 mins and then the layers wereseparated. The organic layer was washed with 1N HCl, saturated NaHCO₃,brine, dried over Na₂SO₄ and concentrated. The crude residue waspurified by flash column chromatography (0-10% EtOAc in hexanes) to givethe desired product (14.3 g, 87%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (t,J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.64 (d, J=8.5 Hz, 1H), 7.17 (dd,J=8.5, 2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H).

Example A(185) 6-Cyclopentyl-6-{2-[3-ethyl-4-(2-methxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126) where6-cyclopentyl-6-{2-[3-ethyl-4-(2-methoxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example A(184)) was substituted in place of6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.09 (t, J=7.6 Hz, 3H), 1.40-1.76 (br m,8H), 2.08 (m, 2H), 2.35 (s, 3H), 2.40 (m, 1H), 2.52 (m, 5H), 2.79 (d,J=14.9 Hz, 1H), 3.33 (s, 3H), 3.67 (t, J=3.0 Hz, 2H), 3.74 (d, J=15.9Hz, 1H), 3.82 (d, J=15.9 Hz, 1H), 4.06 (d, J=3.0 Hz, 2H), 6.83 (d, J=8.1Hz, 1H), 6.97 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 8.70 (s, 1H), 8.85 (s,1H), 10.85 (s, 1H). MS (ESI): 535.20 (M+H⁺).

Example A(186)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-5-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-cyclopentyl-6-[2-(3-ethyl-5-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(from step 2 below) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.29 (t, J=7.6 Hz, 3H), 1.59-1.87 (br m,8H), 2.28 (m, 2H), 2.60-2.73 (m, 12H), 2.96 (d, J=17.9 Hz, 1H), 3.90 (d,J=16.4 Hz, 1H), 4.01 (d, J=16.2 Hz, 1H), 6.60 (s, 1H), 6.65 (s, 1H),6.66 (s, 1H), 7.24 (s, 1H), 9.34 (s, 1H), 11.10 (s, 1H). Anal. Calcd.For C₂₈H₃₄N₄O₄.0.4AcOH: C, 67.21; H, 6.97; N, 10.89. Found: C, 67.48; H,7.05; N, 10.53.

Step 2:6-Cyclopentyl-6-[2-(3-ethyl-5-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where3-bromo-5-ethyl-phenol was substituted in place of4-bromo-2-ethyl-6-fluoro-phenol in step 4 of that example.

¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.6 Hz, 3H), 1.45-1.76 (br m, 8H),1.96 (m, 2H), 2.27 (m, 1H), 2.58 (m, 4H), 2.76 (s, 2H), 3.42 (s, 2H),4.75 (s, 1H), 6.44 (s, 1H), 6.53 (s, 1H), 6.55 (s, 1H). MS (ESI): 329.00(M−H+).

Step 2: 3-Bromo-5-ethyl-phenol

The title compound was prepared as described in the following reference:J. Chem Soc Perkin Trans 1, 1984, 1621-1626.

Example A(187)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-hydroxy-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(124) where6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.06 (t, J=7.3 Hz, 3H), 1.47-1.78 (br m,8H), 1.97 (m, 1H), 2.15 (m, 2H), 2.42-2.69 (m, 11H), 2.80 (d, J=17.6 Hz,1H), 3.74 (s, 3H), 3.78 (d, J=16.4 Hz, 1H), 3.85 (d, J=16.4 Hz, 1H),6.44 (s, 1H), 6.79 (s, 1H), 7.10 (s, 1H), 9.13 (s, 1H), 10.90 (s, 1H).MS (ESI): 521.20 (M+H⁺).

Step 4:6-Cyclopentyl-6-[2-(5-ethyl-2-hydroxy-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(124) where1-benzyloxy-2-bromo-4-ethyl-5-methoxy-benzene (from step 3 below) wassubstituted in place of acetic acid 4-bromo-2-ethyl-6-fluoro-phenylester. MS (ESI): 361.10 (M+H⁺).

Step 3: 1-Benzyloxy-2-bromo-4-ethyl-5-methoxy-benzene

Sodium hydroxide (0.39 g, 9.7 mmol) and hydrazine monohydrate (0.57 mL,11.7 mmol) were added to a solution of1-(4-benzyloxy-5-bromo-2-methoxy-phenyl)-ethanone (1.3 g, 3.9 mmol)dissolved in triethylene glycol (5 mL). The reaction mixture was heatedto 170° C. for 24 hours and then partitioned between 1N HCl and EtOAc.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash silica gelchromatography (0% to 5% EtOAc in hexanes) to give the title compound(0.52 g, 40%). ¹H NMR (400 MHz, CDCl₃): δ 1.14 (t, J=7.3 Hz, 3H), 2.53(q, J=7.3 Hz, 2H), 3.75 (s, 3H), 5.14 (s, 2H), 6.48 (s, 1H), 7.26 (s,1H), 7.32 (m, 1H), 7.39 (m, 2H), 7.49 (d, J=8.3 Hz, 2H).

Step 2: 1-(4-Benzyloxy-5-bromo-2-methoxy-phenyl)-ethanone

A solution of tetrabutyl ammonium tribromide (12.1 g, 25 mmol) in CHCl₃(75 mL) was added to a stirred solution of1-(4-benzyloxy-2-hydroxy-phenyl)-ethanone (6.07 g, 25.1 mmol) dissolvedin CHCl₃ (75 mL). The reaction mixture was stirred for 18 hrs and thenquenched with 5% solution of sodium thiosulfate (100 mL). The biphasicmixture was stirred for 30 mins and then the layers were separated. Theorganic layer was washed with 1N HCl, saturated NaHCO₃, brine, driedover Na₂SO₄ and concentrated to a brown oil.

The oil was dissolved in DMF (30 mL) and treated with potassiumcarbonate (10.4 g, 75.3 mmol) followed by methyl iodide (1.9 mL, 30mmol). The mixture was stirred for 20 hours and then partitioned between1N HCl and EtOAc. The organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The oil was purified by flash columnchromatography (0% to 15% EtOAc in hexanes) to give the desired product(2.39 g, 28%). ¹H NMR (400 MHz, CDCl₃): δ 2.55 (s, 3H), 3.85 (s, 3H),5.23 (s, 2H), 6.48 (s, 1H), 7.32-7.43 (m, 3H), 7.47 (d, J=8.3 Hz, 2H),8.06 (s, 1H).

Step 1: 1-(4-Benzyloxy-2-hydroxy-phenyl)-ethanone

Potassium carbonate (27.2 g, 0.2 mol) followed by benzyl bromide (7.04mL, 59.2 mmol) were added to a solution of1-(2,4-dihydroxy-phenyl)-ethanone (10 g, 66 mmol) in DMF (90 mL): Themixture was stirred for 2 hours and then partitioned between 1N HCl andEtOAc. The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography (0% to 20%EtOAc in hexanes) followed by recrystallization gave the title compoundas a white solid (8.7 g, 55%). ¹H NMR (400 MHz, CDCl₃): δ 2.55 (s, 3H),5.09 (s, 2H), 6.50 (s, 1H), 6.51 (dd, J=9.1, 3.9 Hz, 1H), 7.34-7.43 (m,5H), 7.64 (d, J=9.1 Hz, 1H), 12.73 (s, 1H).

Example A(188)1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopentanecarbonitrile

The title compound was prepared analogously to Example A(97)2-[4-(2-{2-cyclopentyl-5-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrilewhere1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrileExample A(189) was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrileand 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹HNMR (400 MHz, CDCl₃) δ: 1.44-1.96 (m, 17H), 2.14-2.22 (m, 2H), 2.56-2.62(m, 8H), 2.70-2.74 (m, 2H), 3.79 (d, J=16 Hz, 1H), 3.92 (d, J=16 Hz,1H), 7.12 (s, 1H), 7.24 (s, 1H), 7.26 (d, J=5 Hz, 1H), 7.42-7.47 (m,1H), 10.9 (s, 1H). Anal. Calcd. For C₃₂H₃₆FN₅O₃: C, 68.92; H, 6.51; N,12.56. Found: C, 68.74; H, 6.60; N, 12.47. MS (ESI): 558 (M+H)⁺.

Example A(189)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile(

The title compound was prepared analogously to step 4 from Example A(97)where1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile(from step 2 below) was substituted in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (CDCl₃) δ: 1.18-1.74 (m, 16H), 1.92-2.17 (m, 2H), 2.5-2.52 (m,1H), 2.66-2.68 (m, 2H), 2.77 (s, 2H), 3.43 (s, 2H), 6.89-6.94 (m, 2H),7.33-7.37 (m, 1H). MS (ESI): 398 (M+H)⁺.

Step 2:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile

The title compound was prepared analogously to step 3 from Example A(97)where 1-(4-Bromo-2-fluoro-phenyl)-cyclopentanecarbonitrile (described instep 1 below) was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. MS (ESI): 452 (M+H)⁺.

Step 1: 2-(4-Bromo-2-chloro-phenyl)-2-methyl-propionitrile

(4-bromo-2-fluorophenyl)acetonitrile (1 g, 4.67 mmol) described in step1 from Example A(97), benzyltriethylammonium chloride (0.02 g, 0.09mmol) and 1,4-Dibromobutane (1.43 g, 0.79 mmol) were dissolved 50%aqueous NaOH (3 mL) and the resulting mixture was stirred for 3 hours at50° C. Reaction was quenched with 4N HCl (50 mL extracted with EtOAc.The organic phase was dried over Na₂SO₄ and evaporated. The crudeorganic product was purified by flash column chromatography (5% EtOAc inhexanes) to give the product (1.25 g, 100%) as a clear oil). ¹H NMR(CDCl₃) δ: 1.93-2.17 (m, 4H), 2.50-2.55 (m, 2H), 3.42-3.46 (m, 2H),7.26-7.34 (m, 3H).

Example A(190)1-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopentanecarbonitrile

The title compound was prepared analogously to Example A(97) where6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile(Example A(189) (was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃) δ: 1.35-2.16 (m, 16H), 2.42-2.82 (m, 7H), 3.33(s, 3H), 3.74 (d, J=16 Hz, 1H), 3.84 (d, J=16 Hz, 1H), 7.14-7.19 (m,2H), 7.36-7.41 (m, 1H), 8.71 (s, 1H), 9 (s, 1H), 10.9 (s, 1H). Anal.Calcd. For C₃₁H₃₄FN₅O_(3.0.75)H₂O: C, 66.83; H, 6.42; N, 12.57. Found:C, 66.93; H, 6.18; N, 12.45. MS (ESI): 544 (M+H)⁺.

Example A(191)1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopentanecarbonitrile

The title compound was prepared analogously to Example A(97) where6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile(Example A(189) (was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃) δ: 1.41-1.98 (m, 17H), 2.30-2.68 (m, 6H), 3.62(d, J=16 Hz, 1H), 3.71 (d, J=16 Hz, 1H), 6.99-7.03 (m, 2H), 7.21-7.25(m, 1H), 8.74 (s, 1H), 9.45 (s, 1H), 10.8 (s, 1H). Anal. Calcd. ForC₃₀H₃₁ClFN₅O₃: C, 63.88; H, 5.54; N, 12.42. Found: C, 63.73; H, 5.71; N,12.17. MS (ESI): 564 (M+H)⁺.

Example A(192)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(97) where6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Example A(194)) was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrileand 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde inthat example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.5-2.0 (m, 11H) 2.46-2.75(m, 11H), 3.25 (s, 3H), 3.73 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H),4.32 (s, 2H), 6.70 (d, J=8 Hz, 1H), 6.94-7.04 (m, 3H), 9.20 (s, 1H).Anal. Calcd. For C₂₈H₃₄N₄O₅.1.5H₂O: C, 63.02; H, 6.99; N, 10.50. Found:C, 63.92; H, 6.74; N, 10.42. MS (ESI): 507.2 (M+H)⁺.

Example A(193)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(97) where6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Example A(195)) was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrileand 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehydefrom that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.34-2.09 (m, 11H)2.0-2.21 (m, 2H), 2.47-2.74 (m, 10H), 3.74 (d, J=16 Hz, 1H), 3.80 (d,J=16 Hz, 1H), 4.44 (s, 2H), 6.65 (d, J=8 Hz, 1H), 6.88 (d, J=8 Hz, 1H),7.04 (s, 1H), 7.09 (s, 1H), 9.06 (s, 1H). Anal. Calcd. ForC₂₇H₃₂N₄O₅.H₂O: C, 62.96; H, 6.75; N, 10.88. Found: C, 62.97; H, 6.57;N, 10.83. MS (ESI): 493.2 (M+H)⁺.

Example A(194)6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from Example A(97)where Acetic acid2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-benzylester (from step 2 below) was substituted in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.The product was obtained together with Example A(195)6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dionebelow. ¹H NMR (400 MHz, CDCl₃): δ 1.48-1.82 (m, 8H), 1.87-2.09 (m, 3H),2.22-2.28 (m, 1H), 2.55-2.61 (m, 2H), 2.76 (s, 2H), 3.41 (s, 2H), 3.45(2, 3H), 4.62 (2, 2H), 6.78-6.82 (m, 1H), 6.96-6.99 (m, 1H), 7.38 (s,1H). ESIMS (MH−): 345.

Example A(195)6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from Example A(97)where Acetic acid2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-benzylester (from step 2 below) was substituted in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.The product was obtained together with compound from Example A(194).6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dioneabove ¹H NMR (400 MHz, CDCl₃): δ 1.30-1.80 (m, 9H), 1.83-1.86 (m, 2H),2.15-2.18 (m, 1H), 2.49-2.54 (m, 2H), 2.67 (s, 2H), 3.33 (s, 2H), 4.76(s, 2H), 6.71-6.91 (m, 3H). ESIMS (MH−): 331.

Step 2: Acetic Acid2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-benzylEster

The title compound was prepared analogously to step 3 from Example A(97)where Acetic acid 2-acetoxy-5-bromo-benzyl ester (described in step 1below) was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. MS (ESI): 471 (M+H)⁺.

Step 1: 2-(4-Bromo-2-chloro-phenyl)-2-methyl-[1,3]dioxolane

Acetyl chloride (4.38 mL g, 61.56 mmol followed by TEA (8.58 mL, 61.56mmol were added to a solution of 5-bromo-2-hydroxyphenol (5 g, 24.63mmol in CH₂CL₂ (120 mL). The resulting mixture was stirred overnight atroom temperature. The CH₂Cl₂ was then evaporated and residue waspartitioned between EtOAc and 1N HCl. The organic phase was dried overNa₂SO₄ and evaporated. The crude organic product was purified by flashcolumn chromatography (30% EtOAc in hexanes) to give the product (7.07g, 100%) as a pale yellow oil).

¹H NMR (CDCl₃) δ 2.09 (s, 3H), 2.32 (s, 3H), 5.03 (s, 2H), 6.99 (d,J=8.6 Hz, 1H), 7.47 (dd, J=8, 2.3 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H). ESIMS(MH+): 286.2.

Example A(196)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic Example A(146)(2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile.using chiral HPLC: Chiralpak AS-H, 140 Bar, 2.5 mL/min, 35% MeOH. 70%recovery. (3.61 min retention time).

Example A(197)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic Example A(146)(2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile.using chiral HPL (Chiralpak AS-H, 140 Bar, 2.5 mL/min, 35% MeOH. 70%recovery. (12 min retention time).

Example A(198)2-(2-Chloro-4-{2-[5-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97) where6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrilefrom Example A(147) (was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃) δ: 1.17-1.59 (m, 8H), 1.56-1.6 (m, 2H)), 1.82(s, 6H), 1.88-2.01 (m, 2H), 2.31-2.79 (m, 3H), 3.79 (d, J=16 Hz, 1H),3.89 (d, J=16 Hz, 1H), 7.34-7.52 (m, 3H), 8.91 (d, J=2.5 Hz, 1H), 9.63(d, J=2.5 Hz, 1H), 10.9 (s, 1H). C₂₈H₂₉Cl₂N₅O₃: C, 60.65; H, 5.27; N,12.63. Found: C, 60.45; H, 5.19; N, 12.40. MS (ESI): 555.2(M+H⁺).

Example A(199)2-(2-Chloro-4-{2-[2-cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was prepared analogously to Example A(97) where6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrilfrom Example A(147) (was substituted in place of2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl]-2-methylpropanenitrile.¹H NMR (400 MHz, CDCl₃) δ: 1.17-1.59 (m, 8H), 1.59-1.62 (m, 2H)), 1.62(s, 6H), 1.82-2.01 (m, 2H), 2.19 (s, 3H), 2.38-2.65 (m, 3H), 3.55 (d,J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.15-7.32 (m, 3H), 8.53 (d, J=2.3Hz, 1H), 8.82 (s, 1H), 10.7 (s, 1H). C₂₉H₃₂ClN₅O₃: C, 65.22; H, 6.04; N,13.11. Found: C, 65.15; H, 5.99; N, 13.10. MS (ESI): 535.2(M+H⁺).

Example A(200)1-(2-Chloro-4-2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile

The title compound was separated from racemic Example A(148)(1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile.using chiral HPLC (Chiralpak AS-H, 120 Bar, 2.5 mL/min, 35% MeOH). 70%recovery. (2.31 min retention time).

Example A(201)1-(2-Chloro-{42-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5a]pyrimidin2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile

The title compound was separated from racemic Example A(148)(1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile.using chiral HPLC (Chiralpak AS-H, 120 Bar, 2.5 mL/min, 50% MeOH). 70%recovery. (10.26 min retention time).

Example A(202)2-(2-Chloro-4-{2-[2-cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was separated from racemic Example A(199) (usingchiral HPLC (Chiralpak AS-H, 130 Bar, 2.5 mL/min, 25% MeOH. 70%recovery. (7.16 min retention time).

Example A(203)2-(2-Chloro-{42-[2-cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was separated from racemic Example A(199) usingchiral HPL (Chiralpak AS-H, 130 Bar, 2.5 mL/min, 25% MeOH. 70% recovery.(14.71 min retention time).

Example A(204)2-(2-Chloro-{42-[5-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was separated from racemic Example A(198) usingchiral HPLC (Chiralpak AS-H, 140 Bar, 2.5 mL/min, 20% MeOH. 70%recovery. (17.33 min retention time).

Example A(205)2-(2-Chloro-{42-[5-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile

The title compound was separated from racemic Example A(198) usingchiral HPLC (Chiralpak AS-H column, 140 Bar, 2.5 mL/min, 20% MeOH. 70%recovery. (28.93 min retention time).

Example A(206)3-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A (150), where6-ethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (300 MHz, DMSO-d₆) δ: 1.03 (t, J=7.44 Hz, 3H), 1.23 (t, J=7.44Hz, 3H), 1.36-1.74 (m, 8H), 1.89-2.01 (m, 2H), 2.33-2.45 (m, 4H),2.55-2.60 (m, 1H), 2.64-2.79 (m, 4H), 3.62 (s, 3H), 3.72-3.78 (m, 2H),6.37 (s, 1H), 6.75 (s, 1H), 8.73 (d, J=1.88 Hz, 1H), 8.86 (s, 1H), 9.02(s, 1H). Anal. calcd for C₂₉H₃₆N₄O₅ 0.8H₂O: C, 65.10; H, 7.08; N, 10.47.Found C, 65.03; H, 6.77; N, 10.34.

Example A(207)6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-3-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(150), where[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in placeof 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(300 MHz, DMSO-d₆) δ: 0.96 (t, J=7.44 Hz, 3H), 1.30-1.69 (m, 8H),1.81-1.90 (m, 2H), 2.28-2.38 (m, 4H), 2.49-2.52 (m, 1H), 2.65-2.70 (m,1H), 3.55 (s, 3H), 3.70 (s, 2H), 6.29 (s, 1H), 6.68 (s, 1H), 8.70-8.73(m, 1H), 8.94 (s, 1H), 9.03-9.06 (m, 1H). Anal. Calcd forC₂₇H₃₂N₄O₅.0.3H₂O: C, 65.12; H, 6.60; N, 11.25. Found: C, 65.33; H,6.32; N, 10.93.

Example A(208)6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-3-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(207) Condition: ChiralPac AD-H column, 140 bar,25% MeOH, 2.5 mL/min, retention time 13.20 min.

Example A(209)6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-3-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(207) Condition: ChiralPac AD-H column, 140 bar,25% MeOH, 2.5 mL/min, retention time 20.11 min.

Example A(210)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (158). Condition: ChiralPac AS-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 7.77 min.

Example A(211)(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (158). Condition: ChiralPac AS-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 15.0 min.

Example A(212)3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (159). Condition: ChiralPac AS-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 5.65 min.

Example A(213)3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (159). Condition: ChiralPac AS-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 8.77 min.

Example A(214)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(97), where6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (300MHz, DMSO-d₆) δ: 1.44 (s, 6H), 1.52-1.70 (m, 8H), 1.96-2.10 (m, 2H),2.37-2.42 (m, 1H), 2.55-2.64 (m, 3H), 2.74-2.80 (m, 1H), 3.73-3.86 (m,2H), 5.17 (s, 1H), 6.88-6.93 (m, 1H), 6.99-7.02 (m, 1H), 7.47-7.52 (m,1H), 8.86 (d, J=3.0 Hz, 1H), 9.58 (d, J=3.0 Hz, 1H). Anal: calcd forC₂₇H₃₀ClFN₄O₄.0.9H₂O: C, 59.48; H, 5.88; N, 10.28. Found: C, 59.52; H,5.86; N, 9.90.

Example A(215)6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione

To a solution of methyl acetoacetate (3.9 mL, 36.0 mmol) in anhydrousTHF (90 mL) at 0° C. was added NaH (60%, 1.44 g, 36.0 mmol) portionwise.After 10 min, the solution was cooled further to −40° C. n-BuLi (1.6 M,22.5 mL) was added dropwise and the resulting solution was stirred atthat temperature for 30 min. A solution of1-cyclopentyl-3-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]propan-1-one(2.5 g, 9.0 mmol) in THF (4 mL) was added and the mixture was slowlywarmed up to 25° C. and stirred for 4 hours. The reaction was quenchedby the addition of NH₄Cl and the mixture was extracted with EtOAc (3×50mL). The combined organic layers were washed with brine, dried overNa₂SO₄. The solvent was removed and the crude product was taken directlyinto next step without futher purification.

The crude product from previous step was dissolved in THF (40 mL) andthe solution was treated with 2.0 N NaOH (18 mL). The resulting mixturewas stirred at 25° C. for 4 hours before it was quenched by the additionof 1 N HCl. The mixture was extracted with EtOAc (3×30 mL) and thecombined organic layers were washed with brine, dried over Na₂SO₄. Thesolvent was removed and the crude product was purified by columnchromatography to give the desired product in 58% yield (two steps). ¹HNMR (CDCl₃) δ: 1.43-1.77 (m, 8H), 1.62 (s, 6H), 1.92-1.99 (m, 2H),2.23-2.32 (m, 1H), 2.64-2.71 (m, 2H), 2.75-2.78 (m, 2H), 3.41-3.45 (m,2H), 6.81-6.84 (m, 1H), 6.90-6.92 (m, 1H), 7.44-7.48 (m, 1H).

Step 2: Preparation of Compound1-cyclopentyl-3-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]propan-1-one

To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (5.8 g, 25.0mmol) in anhydrous NMP (63 mL) was added 1-Cyclopentyl-2-propen-1-ol(3.15 g, 25.0 mmol), NaHCO₃ (4.2 g, 50 mmol) and PdCl₂(PPh₃)₂ (350 mg, 2mol %). The mixture was heated to 140° C. for 4 hours before it wascooled down to room temperature. The reaction was diluted with aqueousNH₄Cl, extracted with EtOAc (3×50 mL). The combined organic extractswere washed with brine, dried with Na₂SO₄ and evaporated to dryness. Themixture was purified by flash column chromatography (10-50% EtOAc inhexanes) to give the product (2.5 g, 36% yield). ¹H NMR (300 MHz, CDCl₃)δ: 1.56-1.82 (m, 8H), 1.62 (s, 6H), 2.74-2.78 (m, 2H), 2.82-2.89 (m,2H), 6.84-6.88 (m, 1H), 6.93-6.95 (m, 1H), 7.40-7.44 (m, 1H).

Step 1: Preparation of Compound 2-(4-bromo-2-fluorophenyl)propan-2-ol

A solution of 4-bromo-2-fluorobenzoic acid (10 g) in anhydrous MeOH (200mL) was added conc. sulfuric acid (0.5 mL). The mixture was heated toreflux for 15 hours before it was cooled down to room temperature. Thesolvent was removed and the residue was taken up in EtOAc (100 mL) andwashed with sat. NaHCO₃, brine and dried over Na₂SO₄. The crude productwas taken into next step without further purification.

To a solution of methyl 4-bromo-2-fluorobenzoate (12 g, 51.5 mmol) inanhydrous ether (140 mL) at 0° C. was added MeMgBr (3.0 M, 70 g)dropwise. The mixture was slowly warmed up to room temperature andstirred for 3 hours. The reaction was quenched by the addition ofsaturated NH₄Cl and extracted with EtOAc (3×150 mL). The combinedorganic extracts were washed with brine, dried with Na₂SO₄ andevaporated to dryness. The mixture was purified by flash columnchromatography (0-20% EtOAc in hexanes) to give the product (12 g, 95%yield).

¹H NMR (300 MHz, CDCl₃) δ: 1.62 (s, 6H), 7.18-7.23 (m, 1H), 7.25-7.28(m, 1H), 7.44-7.49 (m, 1H).

Example A(216)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(214), where6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹HNMR (400 MHz, DMSO-d₆) δ: 1.25-1.32 (m, 1H), 1.39 (s, 6H), 1.43-1.64 (m,7H), 1.90-2.07 (m, 2H), 2.29 (s, 3H), 2.32-2.36 (m, 2H), 2.46-2.54 (m,2H), 2.67-2.71 (m, 1H), 3.64-3.76 (m, 2H), 6.85 (dd, J=13.14, 1.52 Hz,1H), 6.92 (dd, J=8.08, 1.52 Hz, 1H), 7.43 (m, 1H), 8.62 (d, J=2.27 Hz,1H), 8.88 (dd, J=2.27, 1.01 Hz, 1H). Anal. calcd for C₂₈H₃₃FN₄O₄.1.2H₂O:C, 63.43; H, 6.73; N, 10.57. Found: C, 63.19; H, 6.51; N, 10.41.

Example A(217)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(214), where5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde wassubstituted in place of6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR (400MHz, DMSO-d₆) δ: 1.29-1.34 (m, 1H), 1.39 (s, 6H), 1.44-1.64 (m, 7H),2.02-2.07 (m, 2H), 2.31-2.37 (m, 1H), 2.40 (s, 3H), 2.48 (s, 3H),2.50-2.55 (m, 3H), 2.70-2.74 (m, 1H), 3.63-3.78 (m, 2H), 6.84-6.87 (m,1H), 6.96-6.98 (m, 2H), 7.43-7.47 (m, 1H). Anal. calcd forC₂₉H₃₅FN₄O₄.0.8H₂O: C, 64.86; H, 6.87. Found: C, 64.96; H, 6.61.

Example A(218)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one(enantiomer A)

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(217). Condition: ChiralPac AD-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 6.16 min.

Example A(219)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one(enantiomer B)

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(120). Condition: ChiralPac AD-H column, 140 bar,40% MeOH, 2.5 mL/min, retention time 9.13 min.

Example A(220)6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-3-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(214), whereI[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted inplace of 6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.25-1.32 (m, 1H), 1.39 (s, 6H), 1.43-1.64 (m,7H), 1.91-2.08 (m, 2H), 2.30-2.36 (m, 1H), 2.46-2.55 (m, 3H), 2.68-2.73(m, 1H), 3.67-3.79 (m, 2H), 6.86 (dd, J=13.01, 1.39 Hz, 1H), 6.94 (dd,J=8.08, 1.52 Hz, 1H), 7.19 (dd, J=6.82, 4.29 Hz, 1H), 7.44 (m, 1H), 8.73(dd, J=4.29, 1.77 Hz, 1H), 9.03 (dd, J=6.82, 2.02 Hz, 1H). Anal. calcdfor C₂₇H₃₁FN₄O₄.0.4H₂O: C, 64.63; H, 6.39; N, 11.17. Found: C, 64.63; H,6.15; N, 10.71.

Example A(221)2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), whereimidazo[1,2-a]pyrimidine-2-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆)δ: 1.16-1.45 (m, 8H), 1.56 (s, 6H), 1.78-1.85 (m, 2H), 1.93-1.96 (m,2H), 2.19-2.27 (m, 1H), 2.46-2.51 (m, 3H), 2.62-2.67 (m, 1H), 6.92 (d,J=9.60 Hz, 1H), 7.00 (d, J=11.62 Hz, 1H), 7.19 (t, J=8.46 Hz, 1H), 7.29(s, 1H), 7.69 (s, 1H), 8.66 (s, 1H), 8.94 (d, J=5.81 Hz, 1H). HRMS calcdfor C₂₉H₃₂FN₄O₃(M+H)⁺. 503.2453. Found: 503.2455.

Example A(222)2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile

The title compound was prepared analogously to Example A(97), whereimidazo[1,2-a]pyrimidine-3-carbaldehyde was substituted in place of2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆)δ: 1.24-1.58 (m, 8H), 1.64 (s, 6H), 1.79-1.85 (m, 2H), 2.21-2.31 (m,1H), 2.47-2.60 (m, 3H), 2.71-2.75 (m, 1H), 3.10 (s, 2H), 6.91 (dd,J=8.08, 1.52 Hz, 1H), 7.02 (dd, J=13.01, 1.39 Hz, 1H), 7.26 (t, J=8.46Hz, 1H), 7.55 (dd, J=6.95, 4.42 Hz, 1H), 7.87 (s, 1H), 8.87 (dd, J=4.17,1.39 Hz, 1H), 9.15 (dd, J=6.95, 1.64 Hz, 1H). HRMS calcd forC₂₉H₃₂FN₄O₃(M+H)⁺. 503.2453. Found: 503.2458.

Example A(223)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-one

6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.131 g, 0.72mmol) was added to a solution of example A(228)6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione(0.230 g, 0.60 mmol) in MeOH (10 mL). The reaction mixture was stirredfor 15 mins and then treated with borane-dimethylamine complex (53 mg,0.9 mmoL). After 15 hours the reaction mixture was quenched withconcentrated HCl, and concentrated to a residual oil. Purification byflash column chromatography (EtOAc then 0%-5% MeOH in CH₂Cl₂) gave theproduct as a white solid (17 mg). ¹H NMR (DMSO): δ 1.30-1.80 (brm, 8H),2.08-2.18 (brm, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.15 (m, 2H), 3.47 (m,3H), 6.81 (m, 2H), 7.00(s, 1H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd.For C₂₆H₂₆O₄N₄ClF₃: C, 56.68; H, 4.75, N, 10.17. Found: C, 56.50; H,4.69, N, 10.20.

Example A(224)6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-5,6-dihydro-2H-pyran-2-one

6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.88 g, 0.546mmol) was added to a solution of example A(228)6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione(0.175 g, 0.455 mmol) and borane-dimethylamine complex (53 mg, 0.9 mmoL)in MeOH (10 mL). The reaction was stirred at room temperature for 15hours, after which time the mixture was concentrated to a residual oil,and purified by preparatory HPLC to afford the title compound as a whitesolid (50 mg). ¹H NMR (DMSO): δ 1.35-1.85 (brm, 8H), 2.00-2.20 (brm,3H), 2.50 (s, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.04 (m, 2H), 3.54 (m,3H), 6.81 (m, 2H), 7.00(s, 1H), 8.55 (s, 1H), 8.72 (s, 1H). Anal. Calcd.For C₂₇H₂₉O₄N₄F₃: C, 61.14; H, 5.51, N, 9.06. Found: C, 61.21; H, 5.60,N, 9.14.

Example A(225)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde inthat example. ¹H NMR (DMSO): δ 1.40-1.90 (brm, 8H), 1.99-2.28 (brm, 3H),2.58 (s, 3H), 2.73 (m, 5H), 3.00(m, 2H); 3.10 (m, 2H), 3.47 (m, 3H),6.79 (m, 2H), 7.05(m, 2H), 8.83 (bs, 1H), 10.0 (bs, 1H). Anal. Calcd.For C₂₈H₃₁O₄N₄F₃: C, 61.76; H, 5.74, N, 10.29. Found: C, 61.50; H, 5.50,N, 10.14.

Example A(226)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-one

The title compound was separated from racemic Example A(223),3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-oneusing chiral HPLC (AS-H, 120 Bar, 2.5 mL/min, 30% MeOH). (4.76 minretention time).

Example A(227)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-one

The title compound was separated from racemic Example A(223),3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-4-hydroxy-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}-5,6-dihydro-2H-pyran-2-oneusing chiral HPLC (AS-H, 120 Bar, 2.5 mL/min, 30% MeOH). (9.617 minretention time).

Example A(228)6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(124) where4-bromo-2-(2,2,2-trifluoroethyl)phenol from step 6 below was used inplace of 2-ethyl-5-fluorophenol in that example. ¹H NMR (CDCl₃): δ1.35-1.70 (brm, 6H), 1.93, (brm, 2H), 2.04-2.21 (brm, 3H), 2.83-3.12(brm, 8H), 6.78 (dd, J=2.81 Hz 2H), 6.99 (s, 1H). MS(APCI): 385 (M−H).

Step 6: Preparation of Compound 4-bromo-2-(2,2,2-trifluoroethyl)phenol

Tetrabutylammonium tribromide (6.56 g) was dissolved in chloroform (50ml) and added dropwise to a solution of 2-(2,2,2-trifluoroethyl)phenol(2.4 g) in chloroform (50 ml). The reaction mixture was stirred at roomtemperature for 2 hrs, after which time 5% sodium thiosulfate solution(100 ml) was added and the resultant stirred for 30 mins. The mixturewas then partitioned between dichloromethane (100 ml) and 1N HCl (200ml). The organics were separated and dried over magnesium sulfate. Thesolvent was then removed in vacuuo, the crude residue was then purifiedby column chromatography on silica gel eluting with 90:10 hexanes:ethlacetate to afford the title compound as a yellow oil (3.24 g). ¹H NMR(CDCl₃): δ 3.50 (q, J=21.48 Hz 2H), 6.70 (d, J=2.54 Hz, 1H), 7.32 (d,J=2.54 Hz, 1H), 7.45 (s, 1H).

Step 5: Preparation of Compound 2-(2,2,2-trifluoroethyl)phenol

Sodium Borohydride (0.930 g) was added to a solution of2-(1-chloro-2,2,2-trifluoroethyl)phenol (2.6 g) in THF (30 ml). Thereaction mixture was then stirred for 14 hrs at room temperature underan atmosphere of nitrogen, after which time the reaction was quenchedwith 1N HCl (50 ml) and partitioned between 1NHCl (100) and ethylacetate (200 ml), the organics were separated and dried over magnesiumsulfate, filtered and solvent evaporated in vacuuo to afford titlecompound as a semi solid (2.4 g). ¹H NMR (CDCl₃): δ 3.50 (q, J=21.06 Hz2H), 6.80 (m, 1H), 7.00 (m, 1H), 7.25 (m, 2H).

Step 4: Preparation of Compound 2-(1-chloro-2,2,2-trifluoroethyl)phenol

Thionyl chloride (2.28 ml) was added to a solution of2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (3.0 g) and pyridine (1.23 ml)in toluene (50 ml). The reaction was stirred at room temperature for 1hr, after which time the toluene was removed in vacuuo and the residuepartitioned between ethyl acetate (100 ml) and In HCl (100 ml). Theorganics were separated and dried over magnesium sulfate, filtered andsolvent removed in vacuuo to afford the title compound as a clear oil(3.0 g). ¹H NMR (CDCl₃): δ 5.93 (m, 1H), 6.90 (d, J=4.52 Hz, 1H), 7.10(m, 1H), 7.35 (m, 1H), 7.69 (m, 1H).

Step 3: Preparation of Compound 2-(2,2,2-trifluoro-1-hydroxyethyl)phenol

Boron Tribromide (10 ml) (1M soln in DCM) was added to a solution of2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol (1.5 g) in dichloromethane(20 ml). The reaction mixture was stirres at room temperature under aatmosphere of nitrogen for 56 hrs. The mixture was then partitionedbetween DCM (100 ml) and 1N HCl (100 ml), organics washed with water(100 ml), dried over magnesium sulfate, filtered and solvent removed invacuuo to afford the title compound as a clear yellow oil (1.5 g). ¹HNMR (CDCl₃): δ 3.50 (bs, 1H), 5.25 (m, 1H), 6.73 (bs, 1H), 7.00 (m, 2H),7.32 (d, J=2.56 Hz, 1H), 7.45 (m, 1H).

Step 2: Preparation of Compound2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol

10% palladium on carbon (1.5 g) was added to a solution of2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone (3.0 g) in methanol (50 ml).The resultant was hydrogenated at room temperature for 12 hrs. Afterwhich time the catalyst was filtered off through a plug of celite andthe solvent concentrated in vacuuo. The crude was purified by columnchromatography on silica gel eluting with 100% hexanes the 80:20hexanes:ethylacetate to afford the title compound as a yellow oil (3.0g). ¹H NMR (CDCl₃): δ 3.75 (d, J=2.56 Hz, 1H), 3.96 (s, 3H), 5.35 (m,1H), 7.05 (m, 2H), 7.50 (m, 2H).

Step 1: Preparation of Compound2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone

2 Methoxy Phenyl magnesium bromide (35 ml) was added slowly to asolution of methyl trifluoroacetate (5.0 g) in diethyl ether (100 ml)@−78° C. The reaction mixture was warmed to room temperature over 12 hrsand the quenched with saturated ammonium chloride solution (100 ml). Themixture was then partitioned between ethyl acetate (500 ml) and water(250 ml) The organics were separated and dried over magnesium sulfatefiltered and concentrated in vacuuo. The crude residue was purified bycolumn chromatography on silica gel eluting with 100% hexanes, 90:10 and80:20, hexanes:ethyl acetate, to afford title compound as a yellow oil.(4.0 g).

¹H NMR (CDCl₃): δ 3.57 (s, 3H), 7.00 (m, 2H), 7.35 (m, 1H), 7.63, (d,J=2.54 Hz 2H).

Example A(229)6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-3-[(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.80(brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.68 (s, 1H),2.70(s, 2H); 2.92 (m, 2H), 3.69 (m, 3H), 6.64 (d, J=3.56 Hz, 1H), 6.66(d, J=3.56 Hz, 1H), 7.00 (m, 2H), 8.55 (d, J=6.97 Hz, 1H). Anal. Calcd.For C₂₇H₃₂O₄N₄: C, 68.05; H, 6.77, N, 11.76. Found: C, 68.24; H, 6.80,N, 11.77.

Example A(230) 3-[(6-bromo[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl)dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.90(brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.75 (m, 2H);2.90 (m, 2H), 3.50 (m, 3H), 6.64 (d, J=5.26 Hz, 1H), 6.70 (d, J=5.26 Hz,1H), 7.00 (s, 1H), 8.75 (s, 1H), 9.19 (s, 1H). Anal. Calcd. ForC₂₆H₂₉O₄N₄Br C, 57.68; H, 5.40, N, 10.35. Found: C, 57.50; H, 5.50, N,10.30.

Step 2. 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

A slurry of (6-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (6.5g, 28.51 mmol) from step 1 above in dichloromethane (60 mL) was addedPhI(OAc)₂ (10.1 mg, 31.4 mmol) and with catalytic TEMPO (334 mg, 2.14mmol). After reaction at room temperature for 3 hours, the reaction iscomplete. MTBE is added slowly (50 mL) to crystallize the product,filtration followed by drying the product by vacuum oven overnight. Thefiltrate was concentrated and purified by flash chromatography (2% MeOHin CH₂Cl₂) to give the desired product as light white solid (combinetotal 4.8 g, 75% yield). ¹H NMR (300 MHz, CDCl3) □ ppm 8.96 (d, J=2.45Hz, 1H) 9.09 (d, J=2.45 Hz, 1H) 10.22 (s, 1H). MS: (APCI) 228 (M+H).

Step 1. (6-Bromo-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol

To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (6.29 g, 33.12mmol) in acetic acid (25 ml) was added bromomalonaldehyde (5 g, 33.12mmol). The mixture was heated at 60° C. for hours, and then cooled toroom temperature. The light yellow solid was formed. After the solidwere removed by filtration followed by drying in vacuum oven providesthe light yellow solid as desired product, the filtrate was concentrateby rotary evaporation to give yellow oil. The crude oil was purified byflash chromatography (2% MeOH in CH₂Cl₂) to give the desired product aslight yellow solid (combine total 6.5 g, 86% yield). ¹H NMR (300 MHz,DMSO-D6) δ ppm 4.65 (d, J=5.46 Hz, 2H) 5.50-5.67 (m, 1H) 8.94 (d, J=2.45Hz, 1H) 9.83 (d, J=2.26 Hz, 1H). MS: (APCI) 230 (M+H).

Example A(231)3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Example A(235)) was used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.15 (t, J=3.89 Hz, 6H), 1.30-1.80(brm, 8H), 2.00-2.20 (brm, 5H), 2.43 (q, J=20.06 Hz 4H), 2.85 (m, 4H),3.55 (m, 3H), 6.70 (s, 2H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. ForC₂₈H₃₃O₄N₄Cl, C, 64.05; H, 6.34, N, 10.67. Found: C, 64.35; H, 6.50, N,10.75.

Example A(232)6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Example A(235)) was used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 6H), 1.30-1.80(brm, 8H), 2.00-2.20 (brm, 5H), 2.43 (q, J=19.06 Hz 4H), 2.60 (s, 3H),2.80 (brm, 7H), 3.34 (m, 3H), 6.70 (s, 2H), 6.99 (s, 1H). Anal. Calcd.For C₃₀H₃₈O₄N₄, C, 69.47; H, 7.38, N, 10.80. Found: C, 69.45; H, 7.35,N, 10.75.

Example A(233)6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-3-[(6-methyl[1,2,4]triazolo[1,5-α]pyrimidin-2-yl)methyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Example A(235)) was used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.17 (t, J=2.56 Hz, 6H), 1.30-1.80(brm, 6H), 1.99-2.21 (brm, 5H), 2.45 (q, J=19.06 Hz 4H), 2.50 (s, 3H),2.80 (m, 4H), 3.34 (m, 3H), 6.70 (s, 2H), 8.55 (s, 1H), 8.72 (s, 1H),9.30 (s, 1H). Anal. Calcd. For C₂₉H₃₆O₄N₄, C, 69.03; H, 7.19, N, 11.10.Found: C, 69.00; H, 7.05, N, 11.20.

Example A(234)6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-3-([1,2,4]triazolo[1,5-α]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example A(224) where[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Example A(235)) was used in place of6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dionein that example. ¹H NMR (DMSO): δ 1.20 (t, J=2.56 Hz, 6H), 1.30-1.80(brm, 6H), 2.00-2.18 (brm, 5H), 2.40 (q, J=20.06 Hz 4H), 2.80 (m, 4H),3.45 (m, 3H), 6.70 (s, 2H), 7.17 (d, J=2.54 Hz, 1H), 8.80 (m, 2H), 9.29(s, 1H). Anal. Calcd. For C₂₈H₃₄O₄N₄, C, 68.55; H, 6.99, N, 11.42.Found: C, 68.80; H, 7.31, N, 11.45.

Example A(235)6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(124) where2,6-diethylphenol (Selassie, Cynthia et al. J. Chem. Soc, Perkin Trans2. EN; 2002; 1112-1117) was used in place of 2-ethyl-5-fluorophenol inthat example. ¹H NMR (CDCl₃): δ 1.17 (t, J=9.57 Hz, 6H) 1.30-2.21 (br m,11H), 2.45, (m, 4H), 2.70-3.10 (brm, 6H), 6.69 (s, 2H). MS(APCI): 357(M−H).

Example A(236)1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrile

A solution of example A(237) in anhydrous MeOH (6 mL) was treated with5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.352 g,2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol)at room temperature. The reaction was stirred for 2 hours, and thesolids were filtered away. The organic liquid was concentrated to athick oil, and then purified by flash chromatography (50 g SiO₂,3:10->3:5 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5%hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give thedesired product as an oil. It was further purified by crystallizationfrom ethyl acetate/hexanes to give a white powder (89 mg, 11%). ¹H NMR(400 MHz, CDCl₃) δ: 1.31-1.65 (m, 8H), 1.89-2.00 (m, 4H), 2.28-2.34 (m,1H), 2.36-2.44 (m, 1H), 2.50 (d, J=3.54 Hz, 1H), 2.54-2.65 (m, 6H),2.67-2.78 (m, 7H), 4.08 (d, J=4.80 Hz, 2H), 6.79 (dd, J=11.49 Hz, H),6.84-6.81 (m, 2H), 7.04 (t, J=7.96 Hz, H).

Example A(237)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

To a solution of1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile(6.0 g, 13.7 mmol) from step 3 below was added Pd(OH)₂/C (2.0 g) andethanol (100 mL). The reaction was placed under a nitrogen atmosphereusing a balloon filled with hydrogen. The slurry was stirred vigorouslyfor 18 hours. The reaction was filtered to remove all of the solids, andthe liquid was concentrated to an oil. The oil was dissolved in methanol(100 mL), and solution of NaOH (1.64 g, 41 mmol) dissolved in water (30mL). The reaction was stirred for 18 hours, and then acetic acid (1 mL)was added. The liquid was concentrated to an oil, then redissolved inCH₂Cl₂, and washed with 1 N HCl. The organic layer was dried over MgSO₄,filtered, and then concentrated to give the desired product (4.338 g,83%). MS (ESI): 382 (M−H⁺).

Step 3:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

The title compound was prepared analogously to step 3 from Example A(97)where 1-(4-bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile from step 2below, was substituted in place of2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionitrile in step 3 of thatexample. MS (ESI): 438.0 (M+H⁺).

Step 2: 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile

A solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (4.0 g, 18.7 mmol)from step 1 and 1,3-dibromopropane (2.1 mL, 20.6 mmol) in Et₂O (5 mL)was slowly added to a slurry of NaH (1.64 g, 41.1 mmol, 60% in mineraloil) in DMSO (19 mL) at room temperature, being careful to keep thetemperature below 35 degrees Celsius. The reaction was stirred for 2.5hours, and then poured into 150 mL of saturated ammonium chloride. Tothis mixture was added CH2₂Cl₂, and the layers were separated. Theaqueous layer was extracted with 2×50 mL of CH₂Cl₂, and the organiclayers were combined. After drying the liquid over MgSO₄, the solidswere filtered away, and the organic was concentrated to an oil. It wasfurther purified by flash chromatography (90 g SiO₂, 1:99->1:20(EtOAc/Hexanes) to give the desired product (2.81 g, 59%). ¹H NMR (400MHz, CDCl₃) δ: 2.06-2.16 (m, H), 2.51-2.63 (m, H), 2.66-2.76 (qd, J=9347Hz, 2H), 2.86-2.94 (m, 2H), 7.16-7.22 (t, J=8.21 Hz, H), 7.30-7.41 (m,2H).

Step 1: (4-Bromo-2-fluoro-phenyl)-acetonitrile

To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (10 g, 373 mmol)in DMF (190 mL) and water (10 mL) was added sodium cyanide (2 g, 448mmol). The reaction was heated to 70 degrees Celsius for 3 hours,concentrated to a volume of 100 mL, and then the solution was dilutedwith 100 mL of ethyl acetate. After the solids were removed byfiltration, water (250 mL) was added and the layers were separated. Theorganic layer was further washed with 3×100 mL of water. The organiclayer was dried over MgSO₄, filtered to remove solids, and thenconcentrated. Purification by distillation gave the desired product(37.12 g, 46%). B.P.=72-75 degrees Celsius.

Example A(238)1-[4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile

The title compound was prepared analogously to example A(236)substituting [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, CDCl₃) δ: 1.35-1.56 (m, 8H), 1.79-1.89 (m, 3H), 2.19-2.25 (m,1H), 2.27-2.33 (m, 1H), 2.43-2.54 (m, 5H), 2.59-2.69 (m, 4H), 3.98-4.06(m, 2H), 6.69 (dd, J1=1.52 Hz, J2=11.62 Hz, 1H), 6.76 (dd, J1=7.83 Hz,J2=1.52 Hz, 1H), 6.94 (t, J=7.96 Hz, 1H), 7.11 (dd, J1=6.82 Hz, J2=4.29Hz, 1H), 8.66 (dd, J1=6.69 Hz, J2=1.89 Hz, 1H), 8.71 (dd, J1=4.42 Hz,J2=1.89 Hz, 1H).

Example A(239)1-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrile

The title compound was prepared analogously to example A(236)substituting 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde inplace of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde.¹H NMR (400 MHz, CDCl₃) δ: 1.54-1.82 (m, 8H), 2.01-2.13 (m, 3H),2.38-2.48 (m, 2H), 2.48-2.57 (m, 4H), 2.67-2.77 (m, 4H), 2.82-2.85 (m,1H), 2.88 (d, J=6.06 Hz, 2H), 4.19 (s, 2H), 6.92 (dd, J1=11.62 Hz,J2=1.26 Hz, 1H), 6.99 (d, J=8.08 Hz, 1H), 7.17 (t, J=7.96 Hz, 1H), 8.69(s, 1H), 8.78 (d, J=1.52 Hz, 1H).

Example A(240)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-propionitrile

The title compound was prepared analogously to example A(236)substituting2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-propionitrilefrom example A(241) in place of1-(4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrileand 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. ¹H NMR(400 MHz, CDCl₃) δ: 1.66-2.00 (m, 8H), 2.30 (s, 2H), 2.36 (s, 2H),2.49-2.62 (m, 4H), 2.69-2.85 (m, 3H), 3.49-3.59 (m, 1H), 3.89-3.94 (m,1H), 4.014.08 (m, 2H), 4.18 (s, 1H).

Example A(241)2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-propionitrile

The title compound was prepared analogously to example A(237)substituting2{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-propionitrilefrom step 2 below in place of1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile.¹H NMR (400 MHz, CDCl₃) δ: 1.33-1.50 (m, 3H), 1.56 (d, J=7.33 Hz, 3H),1.62-1.75 (m, 5H), 1.85-1.93 (m, 2H), 2.15-2.26 (m, 1H), 2.58-2.68 (m,3H), 2.72 (d, J=6.57 Hz, 2H), 3.38 (d, J=3.54 Hz, 2H), 4.09 (q, J=7.33Hz, 1H), 6.84 (d, J=11.12 Hz, 1H), 6.93 (d, J=7.83 Hz, 1H), 7.34 (t,J=7.83 Hz, 1H).

Step 2:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-propionitrile

The title compound was prepared analogously to1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrilein step 3 of example A(236) substituting2-(4-bromo-2-fluoro-phenyl)-propionitrile from step 1 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile. MS (ESI): 437.0(M+H⁺).

Step 1: 2-(4-Bromo-2-fluoro-phenyl)-propionitrile

The title compound was prepared analogously to1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile in step 2 of exampleA(236) substituting iodomethane in place of 1,3-dibromopropane. MS(APCI): 253 (M+H⁺), 255 (M+2+H+).

Example A(242)(+)-1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(113). Optical rotation determined to be (+).

Example A(243)(−)-1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(113). Optical rotation determined to be (−).

Example A(244)(+)-1-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl]-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(114). Optical rotation determined to be (+).

Example A(245)(−)-1-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(114). Optical rotation determined to be (−).

Example A(246)(+)-1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(115). Optical rotation determined to be (+).

Example A(247)(−)-1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(115). Optical rotation determined to be (−).

Example A(248)(+)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was prepared by using chiral SFC to separate theracemic example A(111) Optical rotation determined to be (+).

Example A(249)(−)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

The title compound was prepared by using chiral SFC to separate theracemic A(15). Optical rotation determined to be (−).

Step 2: Preparation of Compound6-chloro[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

A mixture of (6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol(9.86 g, 53.4 mmol), TEMPO (626 mg, 4.01 mmol), iodobenzene diacetate(18.9 g, 58.76 mmol) in CH₂Cl₂ (75 mL) was stirred at room temperaturefor 2 hours. Once the reaction was deemed complete, methyl-tert-butylether (50 mL) was added slowly to precipitate the product. as a whilesolid (8.72 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ: 8.93 (d, J=2.45 Hz, 1H),8.99 (d, J=2.64 Hz, 1H), 10.25 (s, 1H). MS (APCI): 183.0, 185.0 (M+H⁺).

Step 1: Preparation of Compound(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol

To a slurry of (3-amino-1H-1,2,4-triazol-5-yl)methanol (28.5 g, 150mmol) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). Themixture was heated to 80° C. for 4 hours. Upon cooling of the reactionto room temperature, the product crystallized out as a white solid (25.5g, 92%). ¹H NMR (300 MHz, DMSO-D6) δ: 4.67 (s, 2H), 5.62 (s, 1H), 8.94(d, J=2.45 Hz, 1H), 9.81 (d, J=2.45 Hz, 1H). MS (APCI): 185.0 (M+H⁺).

Example A(250)(−)-1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile.Optical rotation determined to be (−).

Example A(251)(+)-1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The title compound was prepared by using chiral SFC to separate theracemic1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile.Optical rotation determined to be (+).

Example A(252)2-(4-{2-[2-Cyclopentyl-5-(6-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile(3428-187 PF-00389530)

A solution of2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile(272 mg, 0.7 mmol) in anhydrous MeOH (1.5 mL) was treated with6-ethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0mmol), followed by borane-dimethylamine complex (191.7 mg, 1.05 mmol) atroom temperature. The reaction was stirred for 12 hours. The precipitatewas removed by filtration, and the filtrate was concentrated to a crudeoil. The crude oil was purified by flash chromatography (25 g SiO₂,1:3:1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5%hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to giveproduct as an oil. It was further purified by preparatory HPLC. Yield:19.0 mg, 8.0%. ¹H NMR (CDCl₃) δ: 1.37 (t, J=3.75 Hz, 3H)), 1.48-1.75 (m,8H), 1.84 (s, 6H), 1.91-2.02 (m, 2H), 2.32-2.49 (m, 3H), 2.61-2.70 (m,2H), 2.79-2.86 (m, 2H), 4.10 (s, 2H), 6.69 (d, J=10.86 Hz, 2H), 8.62 (s,1H), 8.73 (s, 1H). MS (ESI): 548 (M−H).

Example A(253)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile(3428-020 PF-00460708)

The desired product was prepared analogously to Example A (112),substituting 5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(86.0 mg, 0.53 mmol) in place of5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield: 66.0mg, 14%. ¹H NMR (CDCl₃) δ: 0.88 (t, J=3.4 Hz, 2H), 1.20-1.41 (m, 6H),1.84 (s, 6H), 1.94-2.03 (m, 2H), 2.31-2.48 (m, 2H), 2.64 (t, J=3.18 Hz,2H), 2.74 (s, 3H), 4.09 (s, 2H), 6.70 (d, J=11.1 Hz, 2H), 7.03 (d, J=9.8Hz, 1H), 8.67 (d, J=7.0 Hz, 1H). MS (ESI): 534 (M−1).

Example A(254)2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile(3428-192 PF-00398981)

The desired product was prepared analogously to Example A (112),substituting1{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}cyclopropanecarbonitrilein place of2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile.Yield: 18.0 mg, 5.0%. ¹H NMR (CDCl₃) δ: 1.34 (t, J=2.50 Hz, 2H),1.63-1.74 (m, 9H), 1.81-1.91 (m, 2H), 2.36-2.44 (m, 4H), 2.49 (s, 3H),2.64-2.74 (m, 4H), 4.10 (s, 2H), 6.70 (d, J=7.4 Hz, 2H), 8.62 (d, J=2.3Hz, 1H), 8.70 (d, J=2.2 Hz, 1H). MS (ESI): 532 (M−1).

Example A(255)1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-cyclopropanecarbonitrile

The desired product was prepared analogously to step of example A (97),substituting144-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-cyclopropanecarbonitrile(1.0 g, 2.66 mmol) from Step 2 below in place of2{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.Yield: 0.43 g, 42%. δ: ¹H NMR (CDCl₃) δ: 1.35 (t, J=2.8 Hz, 2H),1.56-1.73 (m, 10H), 1.92 (t, J=4.45 Hz, 2H), 2.21-2.30 (m, 1H),2.65-2.79 (m, 4H), 3.44 (d, J=5.6 Hz, 2H), 6.71(d, J=8.6 Hz, 2H). MS(ESI): 386 (M−1).

Step 2:1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluoro-phenyl}-cyclopropanecarbonitrile

The desired product was prepared analogously to Example A (97) step 3,substituting 1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile(1.0 g, 4.16 mmol) from step 1 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 1.2 g,80.0%. ¹H NMR (CDCl₃) δ: 1.37 (t, J=2.8 Hz, 2H), 1.62-1.70 (m, 6H), 1.72(s, 3H), 1.73 (s, 3H), 1.74-1.83 (m, 4H), 2.22-2.27 (m, 1H), 2.66 (s,2H), 5.44 (s, 1H), 6.92 (d, J=8.0 Hz, 2H). MS (ESI): 440 (M−1).

Step 1: 1-(4-Bromo-2,6-difluoro-phenyl)-cyclopropanecarbonitrile

The desired product was prepared analogously to Example A (141) step 3,substituting 1,2-bromoethane in place of Mel. Yield: 1.0 g, 74.4%. ¹HNMR (CDCl₃) δ: 1.36 (t, 2.8 Hz, 2H), 1.77 (t, J=2.7 Hz, 2H), 7.13 (d,J=6.8 Hz, 2H).

Example A(256)1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-cyclopropanecarbonitrile

The desired product was prepared analogously to Example A (112),substituting 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(180.9 mg, 1.0 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:85.0 mg, 23%. ¹H NMR (CDCl₃) δ: 1.34 (t, J=2.70 Hz, 2H), 1.69-1.71 (m,4H), 1.94-1.99 (m, 3H), 2.35-2.49 (m, 4H), 2.65-2.78 (m, 4H), 3.42 (d,J=3.8 Hz, 2H), 4.11 (d, J=4.0 Hz, 2H), 6.70 (d, J=4.6 Hz), 8.80 (s, 1H),8.87 (s, 1H).

MS (ESI): 552 (M−1).

Example A(257)(+)-2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (143) Condition: ChiralPac AS-H column, 250×4.6mm, 120 bar, 30% MeOH, 50 mL/min, retention time 4.84 min.

Example A(258)(−)-2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile(3428-175 PF-00419774)

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (143) Condition: ChiralPac AS-H column, 250×4.6mm, 120 bar, 30% MeOH, 50 mL/min, retention time 2.85 min.

Example A(259)(+)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (142) Condition: ChiralPac AS-H column, 250×20mm, 110 bar, 30% MeOH, 2.5 mL/min, retention time 4.86 min.

Example A(260)(−)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (142) Condition: ChiralPac AS-H column, 250×20mm, 110 bar, 30% MeOH, 2.5 mL/min, retention time 3.31 min.

Example A(261)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-5-methoxy-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to Example A (112),substituting2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,-dihydro-2H-pyran-2-yl)-ethyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrilefrom Step 4 below in place of2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile.Yield: 0.071 g, 16%. ¹H NMR (CDCl₃) δ: 1.54-1.63 (m, 4H), 1.77 (s, 6H),1.91-1.97 (s, 4H), 2.37-2.45 (m, 1H), 2.48 (s, 3H), 2.57-2.80 (m, 4H),3.75-3.85 (m, 5H), 4.10 (d, J=5.5 HZ, 2H), 6.84 (d, J=2.1 Hz, 1H), 6.89(d, 6.6 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H). MS(ESI): 546 (M−1).

Step 4:2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to Example A (97), step 4,substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrile(2.0 g, 4.39 mmol) from Step 6 below in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.Yield: 0.87 g, 49%. ¹H NMR (CDCl₃) δ: 1.39-1.48 (m, 2H), 1.59-1.68 (m,5H), 1.79 (s, 6H), 1.83-1.95 (m, 3H), 2.30-2.37 (m, 1H), 2.54-2.69 (m,4H), 3.83 (s, 3H), 5.30 (s, 1H), 6.86 (d, J=11.9 Hz, 1H), 6.95 (d, J=6.6Hz, 1H). MS (ESI): 400 (M−1).

Step 6:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrile

The desired product was prepared analogously to Example A (97) step 3,substituting 2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile (5.2g, 20.32 mmol) from step 5 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 8.7 g,96.0%. ¹H NMR (CDCl₃) δ: 1.50-1.61 (m, 8H), 1.72 (s, 3H), 1.75 (s, 3H),1.80 (s, 6H), 2.20-2.29 (m, 1H), 2.61 (s, 1H), 2.65 (d, J=9.1 Hz, 2H),3.87 (s, 3H), 5.53 (s, 1H), 7.00 (d, J=6.5 Hz, 1H, 7.03 (d, J=111.6 Hz,1H). MS (ESI): 454 (M−1).

Step 5: 2-(4-Bromo-2-fluoro-5-methoxy-phenyl)-2-methyl-propionitrile

The desired product was prepared analogously to Example A (97) step 2,substituting (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile (1.9 g,8.0 mmol) from step 4 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 8.7 g,96.0%. ¹H NMR (CDCl₃) δ: 1.34 (s, 6H), 3.92 (s, 3H), 7.06 (d, J=6.8 Hz,1H), 7.33 (d, J=10.6 Hz, 1H).

Step 4: (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile

The desired product was prepared analogously to Example A (97) step 1,substituting (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile (1.9 g,8.0 mmol) from step 3 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 2.26 g,99.9%. ¹H NMR (CDCl₃) δ: 3.74 (s, 2H), 3.91 (s, 3H), 6.95 (d, J=6.4 Hz,1H), 7.35 (d, J=4.6 Hz, 1H).

Step 3: 1-Bromo-4-bromomethyl-5-fluoro-2-methoxy-benzene

The desired product was prepared analogously to Example A (141) step 1,substituting (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile (1.9 g,8.0 mmol) from step 3 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 2.45 g,82.2%. ¹H NMR (CDCl₃) δ: 3.82 (s, 3H), 4.40 (s, 2H), 6.82 (d, J=5.8 Hz,1H), 7.24 (d, J=10.58 Hz, 1H).

Step 2: (4-Bromo-2-fluoro-5-methoxy-phenyl)-methanol

To a solution of 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (4.03 g, 17.33mmol) from step (1) below in Methanol at 0° C. was added NaBH₄ (0.65 g,17.33 mmol). After the reaction mixture was stirred at 0° C. for 2hours, it was allowed to warm to room temperature. The organic layer wastaken up in ethyl ether, washed with water and dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography (25-45% EtOAc in hexanes) to give the product. Yield:3.90 g, 99.0%. ¹H NMR (CDCl₃) δ: 3.90 (s, 3H), 4.74 (d, J=6.02 Hz, 2H),6.82 (d, J=6.1 Hz, 1H), 7.29 (d, J=10.58 Hz, 1H).

Step 1: 4-Bromo-2-fluoro-5-methoxy-benzaldehyde

Bromine (15 ml, 300 mmol) was added slowly to a solution of2-Fluoro-5-methoxy-benzaldehyde (23.12 g, 150 mmol) in chloroform (500ml), and the mixture was stirred at room temperature for 5 days. Themixture was poured into water (200 ml) and extracted with chloroform(2×200 mL). The organics were washed with water (200 mL) and brine (200mL), dried over MgSO₄, filtered and concentrated. The residue waspurified by flash column chromatography (2-16% EtOAc in hexanes) to givethe product. Yield: 20.7 g, 60%. ¹H NMR (CDCl₃) δ: 3.93 (s, 3H),7.08-7.13 (m, 1H), 7.29 (d, J=12.4 Hz, 1H).

Example A(262)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A (112),substituting 6-Methyl-[1,2,4]triazolo [1,5-a]pyrimidine-2-carbaldehyde(243.2 mg, 1.5 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:178.0 mg, 32%. ¹H NMR (CDCl₃) δ: 1.01 (tt, J=3.75, 3.70 Hz, 6H),1.32-1.58 (m, 6H), 1.99-2.09 (m, 5H), 2.19-2.43 (m, 4H), 2.49 (s, 3H),2.63-2.79 (m, 4H), 4.10 (s, 2H), 6.68 (d, J=11.1 Hz, 2H), 8.63 (s, 1H),8.70 (s, 1H).

MS (ESI): 562 (M−1).

Step 3:2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A (97), step 4,substituting2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-2-ethyl-butyronitrile(3.11 g, 6.55 mmol) from Step 2 below in place of2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile.Yield: 1.52 g, 56%. ¹H NMR (CDCl₃) δ: 1.03 (t, J=3.65 Hz, 6H), 1.18-1.29(m, 2H), 1.38-142 (m, 1H), 1.60-1.82 (m, 4H), 1.92-2.09 (m, 5H),2.23-2.29 (m, 3H), 2.63-2.80 (m, 4H), 3.45 (d, J=3.6 Hz, 2H) 6.73 (d,J=10.8 Hz, 2H). MS (ESI): 416 (M−1).

Step 2:2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluoro-phenyl}-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A (97) step 3,substituting 2-(4-Bromo-2,6-difluoro-phenyl)-2-methyl-propionitrile (5.2g, 20.32 mmol) from step 1 below in place of1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 3.0 g,58.0%. ¹H NMR (CDCl₃) δ: 1.04 (t, J=3.65 Hz, 6H), 1.17-1.39 (m, 3H),1.57-1.67 (m, 1H), 1.73 (s, 3H), 1.74 (s, 3H), 1.82-1.87 (m, 1H),2.02-2.07 (m, 4H), 2.22-2.29 (m, 4H), 2.57 (s, 1H), 2.66 (s, 2H), 5.45(s, 1H), 6.93 (d, J=10.3 Hz, 2H). MS (ESI): 470 (M−1).

Step 1: 2-(4-Bromo-2,6-difluoro-phenyl)-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A (141) step 3,substituting bromoethane in place of Mel. Yield: 3.1 g, 91.4%. ¹H NMR(CDCl₃) δ: 1.04 (t, J=3.65 Hz, 6H), 2.01-2.07 (m, 2H), 2.20-2.27 (m,2H), 7.13 (d, J=9.3 Hz, 2H).

Example A(263)(+)-2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-ethyl-butyronitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (262) (4649-011 PF-00433966) Condition: ChiralPacAS-H column, 250×4.6 mm, 120 bar, 30% MeOH, 2.5 mL/min, retention time4.62 min.

Example A(254)(−)-2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-ethyl-butyronitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (262) Condition: ChiralPac AS-H column, 250×4.6mm, 120 bar, 30% MeOH, 2.5 mL/min, retention time 2.54 min.

Example A(265)2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile

The desired product was prepared analogously to Example A (112),substituting 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(273.9 mg, 1.5 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:70.0 mg, 12%. ¹H NMR (CDCl₃) δ: 1.01 (tt, J=3.7, 3.7 Hz, 6H), 1.49-1.72(m, 8H), 1.97-2.06 (m, 4H), 2.21-2.27 (m, 2H), 2.20-2.34 (m, 1H), 2.49(d, J=14.71 Hz, 1H), 2.66 (t, J=4.15 Hz, 2H), 2.84 (d, J=17.1 Hz, 1H),4.10 (s, 2H), 6.70 (d, J=11.1 Hz, 2H), 8.80 (s (1H), 8.90 (s, 1H). MS(ESI): 583 (M−1).

Example A(266)(+)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (265) Condition: ChiralPac AS-H column, 250×4.6mm, 120 bar, 30% MeOH, 2.5 mL/min, retention time 4.69 min.

Example A(267)(−)-2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile)

The title compound was isolated by chiral SFC of racemic materialdescribed in example A (265) Condition: ChiralPac AS-H column, 250×4.6mm, 120 bar, 30% MeOH, 2.5 mL/min, retention time 2.90 min.

Example A(268)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-N-ethyl-isobutyramide

The desired product was prepared analogously to Example A (112),substituting 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(243.2 mg, 1.5 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:66.0 mg, 14.0%. ¹H NMR (CDCl₃) δ: 1.05 (t, J=3.7 Hz, 2H), 1.52 (s, 6H),1.60-1.76 (m, 2H), 2.02-2.09 (m, 4H), 2.36-2.44 (m, 2H), 2.48 (s, 3H),2.62-2.79 (m, 4H), 3.15-3.27 (m, 3H), 4.05 (S, 2H), 6.81 (d, J=11.4 Hz,1H), 6.94 (d, J=6.8 Hz, 1H), 7.20-7.22 (m, 1H), 8.61 (d, J=2.1 Hz, 1H),8.69 (d, J=2.3 Hz, 1H). MS (ESI): 562 (M−1).

Example A(269)6-Cyclopentyl-6-{2-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-ethyl}-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The desired product was prepared analogously to Example A (112),substituting 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(243.2 mg, 1.5 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:35.0 mg, 10.0%. ¹H NMR (CDCl₃) δ: 1.35 (s, 6H), 1.53-1.77 (m, 6H),1.99-2.05 (m, 4H), 2.32-2.44 (m, 2H), 2.48 (s, 3H), 3.75 (s, 2H), 4.08(s, 2H), 6.80 (dd, J=13.19, 1.6 Hz, 1H), 7.00 (dd, J=10.5, 1.8 Hz, 1H),7.20-7.24 (m, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H). MS(ESI): 521 (M−1).

Example A(271)2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl)-2-fluoro-phenyl)-2-methyl-propionicAcid Methyl Ester

The desired product was prepared analogously to Example A (112),substituting 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(176.0 mg, 0.967 mmol) in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield:29.0 mg, 4.0%. ¹H NMR (CDCl₃) δ: 1.35-1.44 (m, 2H), 1.53 (s, 6H),1.55-1.74 (m, 8H), 2.41-2.46 (m, 2H), 2.49 (s, 3H), 2.63-2.79 (m, 3H),3.66 (s, 3H), 4.10 (s, 2H), 6.80 (dd, J=10.4, 1.8 Hz, 1H), 6.93 (dd,J=9.6, 1.5 Hz, 1H), 7.19-7.24 (m, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.70 (d,J=2.3 Hz, 1H). MS (ESI): 549 (M−1).

Example A(271)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(127) Condition: ChiralPac AD-H column, 140 bar,25% MeOH, 2.5 mL/min.

Example A(272)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was isolated by chiral SFC of racemic materialdescribed in example A(127) Condition: ChiralPac AD-H column, 140 bar,25% MeOH, 2.5 mL/min.

Example A(273) Enantiomer 1 of6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one,(280 mg) using chiral HPLC (Chiralpak AS-H, 140 bar, 2.5 mL/min, 40%MeOH) (113 mg, 5.140 min retention time).

Example A(274) Enantiomer 2 of6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was separated from racemic6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(280 mg) using chiral HPLC (Chiralpak AS-H, 140 bar, 2.5 mL/min, 40%MeOH) (106 mg, 8.992 min retention time).

Example A(275)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(27) where6-Cyclopentyl-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-dihydro-pyran-2,4-dionefrom step 2 below was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆) δ: 1.14 (t, J=7.6 Hz, 3H), 1.40-1.73 (br m,8H), 2.14 (m, 2H), 2.44-2.67 (m, 12H), 2.78 (d, J=17.7 Hz, 1H), 3.72 (d,J=16.4 Hz, 1H), 3.83 (d, J=16.2 Hz, 1H), 7.04 (s, 1H), 7.50 (s, 1H),8.25 (s, 2H), 10.90 (s, 1H).

Step 2:6-Cyclopentyl-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(1) where3-bromo-5-ethyl-pyridine (from step 1 below) was substituted in place of2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile in step 3 of thatexample. MS (ESI): 316.10 (M+H)⁺.

Step 1: 3-Bromo-5-ethyl-pyridine

Sodium hydroxide (10 g, 0.25 mol) and hydrazine monohydrate (10 mL) wereadded to a solution of 3-acetyl-5-bromopyridine (5 g, 25 mmol) dissolvedin diethylene glycol (18 mL). The reaction mixture was heated to 140° C.for 6 hours and then partitioned between H₂O and Ether. The organiclayers were washed with brine, dried over MgSO₄ and concentrated. Theresidue was purified by flash silica gel chromatography (0% to 40% EtOAcin hexanes) to give the title compound (3 g, 65%). ¹H NMR (400 MHz,CDCl₃): δ 1.26 (t, J=7.6 Hz, 3H), 2.65 (q, J=7.6 Hz, 2H), 7.67 (s, 1H),8.37 (s, 1H), 8.51 (s, 1H).

Section B: Pyrone Prepared by Heck Route

Example B(1):6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a-pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling the6-Cyclopentyl-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 below, to5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): δ 1.39-1.71 (br m, 8H), 2.11 (m, 2H), 2.40 (m, 10H),2.76 (d, 1H, J=17.5 Hz), 3.71 (d, 1H, J=16.2 Hz), 3.80 (s, 3H), 3.85 (d,1H, J=16.2 Hz), 7.05 (m, 4H), 10.83 (s, 1H). Anal. Calcd. ForC₂₇H₃₁N₄O₄F-0.5H₂O: C, 64.40; H, 6.41; N, 11.13. Found: C, 64.33; H,6.34, N, 11.12.

Step 1:6-Cyclopentyl-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-Bromo-2-fluoroanisole was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.43-1.82 (brm, 8H), 1.92 (m, 2H), 2.27 (m, 1H), 2.62(t, J=8.5 Hz, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 3.86 (s, 3H), 6.85 (m,3H). Anal. Calcd. For C₁₉H₂₃FO₄: C, 68.24; H, 6.93. Found: C, 68.46; H,6.84.

Example B(2):6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.33 (t, 3H, J=7.0 Hz), 1.39-1.71 (br m, 8H), 2.11(m, 2H), 2.40-2.58 (m, 10H), 2.78 (d, 1H, J=17.5 Hz), 3.72 (d, 1H,J=16.1 Hz), 3.84 (d, 1H, J=16.1 Hz), 4.06 (q, 2H, J=7.0 Hz), 7.05 (m,4H), 10.90 (s, 1H). Anal. Calcd. For C₂₈H₃₃N₄O₄F-0.4 AcOH: C, 64.94; H,6.55; N, 10.52. Found: C, 65.05; H, 6.53, N, 10.55.

Step 1:6-Cyclopentyl-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where4-Bromo-1-ethoxy-2-fluoro-benzene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example.

Example B(3)6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling the6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.29 (s, 9H), 1.46-1.76 (br m, 8H), 2.19 (m, 2H),2.47 (s, 3 Hz), 2.56-2.70 (m, 7H), 2.87 (d, 1H, J=17.5 Hz), 3.80 (d, 1H,J=16.2 Hz), 3.90 (d, 1H, J=16.2 Hz), 7.12 (m, 2H), 7.28 (m, 3H), 10.92(s, 1H). Anal. Calcd. For C₃₀H₃₈N₄O₃.0.4 AcOH: C, 70.24; H, 7.58; N,10.64. Found: C, 70.27; H, 7.42, N, 10.59.

Step 1:6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), wheretrifluoro-methanesulfonic acid 3-tert-butyl-phenyl ester was substitutedin place of 4-bromo-2-fluoro-1-isopropylbenzene of that example.

¹H NMR (CDCl₃): δ 1.31 (s, 9H), 1.35-1.81 (m, 4H), 1.97 (m, 2H), 2.29(m, 1H), 2.68 (t, 2H, J=8.7 Hz), 2.78 (s, 2H), 2.86 (s, 2H), 3.42 (s,2H), 4.08 (s, 2H), 6.96 (m, 1H), 7.15 (s, 1H), 7.23 (m, 2H). Anal.Calcd. For C₂₂H₃₀O₃.0.10H₂O: C, 76.75; H, 8.84. Found: C, 76.89; H,9.03. ESIMS (M−H⁻¹): 341.2.

Example B(4)6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example A(18)) to5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹HNMR (DMSO-d₆): d 1.39-1.72 (br m, 8H), 2.19 (m, 2H), 2.21 (s, 3H),2.39 (s, 3 Hz), 2.47-2.70 (m, 10H), 2.81 (d, 1H, J=17.5 Hz), 3.71 (d,1H, J=16.1 Hz), 3.85 (d, 1H, J=16.2 Hz), 7.04 (s, 1H), 7.27 (d, 2H,J=8.1 Hz), 7.36 (d, 2H, J=8.1 Hz), 10.98 (s, 1H). Anal. Calcd. ForC₃₁H₃₅N₅O₄.0.6H₂O: C, 67.39; H, 6.61; N, 12.68. Found: C, 67.39; H,6.52, N, 12.45.

Example B(5):6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(4-[1,2,3]thiadiazol-4-yl-benzyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling the6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneto 4-[1,2,3]thiadiazol-4-yl-benzaldehyde using the Me₂NHBH₃ methoddescribed in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.36-1.71 (br m, 8H), 1.92 (m, 2H), 2.37 (m, 1H),2.56 (m, 3H), 2.84 (d, 1H, J=17.5 Hz), 3.60 (d, 1H, J=14.3 Hz), 3.71 (d,1H, J=14.3 Hz), 3.79 (s, 3H), 6.96 (s, 2H), 7.19 (s, 1H), 7.41 (d, 2H,J=8.1 Hz), 8.08 (d, 2H, J=8.3 Hz), 9.59 (s, 1H), 11.01 (s, 1H) Anal.Calcd. For C₂₈H₂₉N₂O₄ClS.0.75H₂O: C, 62.44; H, 5.71; N, 5.20. Found: C,62.43; H, 5.58; N, 5.30.

Example B(6):6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-[4-(2,5-dimethyl-pyrrol-1-yl)-benzyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneto 4-(2,5-Dimethyl-pyrrol-1-yl)-benzaldehyde using the Me₂NHBH₃ methoddescribed in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): δ 1.32-1.66 (br m, 8H), 1.89 (m, 2H), 1.90 (s, 6H),2.30 (m, 1H), 2.52 (m, 2H), 2.61 (d, 1H, J=17.7 Hz), 2.79 (d, 1H, J=17.7Hz), 3.57 (d, 1H, J=14.4 Hz), 3.65 (d, 1H, J=14.4 Hz), 3.80 (s, 3H),5.77 (s, 2H), 7.01 (t, 1H, J=8.6 Hz), 7.10 (t, 1H, J=8.4 Hz), 7.10 (d,2H, J=8.3 Hz), 7.21 (s, 1H), 7.31 (d, 2H, J=8.1 Hz), 10.91 (s, 1H) Anal.Calcd. For C₃₂H₃₆N₁O₄C_(10.5)H₂O: C, 70.77; H, 6.887; N, 2.58. Found: C,70.92; H, 6.79; N, 2.54.

Example B(7)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(from Example A(22)) to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 0.96 (t, 3H, J=7.4 Hz), 1.30-1.58 (br m, 8H), 1.95(m, 2H), 2.41 (m, 12H), 2.63 (d, 1H, J=17.5 Hz), 3.61 (d, 1H, J=15.8Hz), 3.72 (d, 1H, J=15.8 Hz), 6.52 (d, 1H, J=8.1 Hz), 6.74 (m, 2H), 6.93(s, 1H), 8.84 (s, 1H). Anal. Calcd. For C₂₈H₃₄N₄O₄.0.5 AcOH: C, 66.90;H, 6.97; N, 10.76. Found: C, 66.89; H, 6.97, N, 10.83.

Example B(8)6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Example A(2), to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described in thesynthesis of Example B(31)¹H NMR (CDCl₃): δ 1.37 (s, 9H), 1.43-1.86 (brm, 8H), 1.93-2.05 (m, 2H), 2.37 (m, 1H), 2.53-2.79 (m, 10), 3.49 (s,2H), 4.06 (d, J=15.4 Hz, 1H), 4.11 (d, J=15.4 Hz, 1H), 6.58 (d, J=8.1 Hz1H)), 6.81-6.84 (m, 2H), 7.00 (s, 1H).

Example B(9)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-methoxy-3-methyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(4-methoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 below to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described inExample B(31). ¹H NMR (CDCl₃): δ 1.52-1.92 (brm, 8H), 2.05 (m, 2H), 2.16(s, 3H), 2.35 (m, 1H), 2.51-2.71 (m, 8H), 2.79 (s, 3H), 3.78 (s, 3H),4.05 (d, J=15.6 Hz, 1H), 4.12 (d, J=15.6 Hz, 1H), 6.71 (d, J=8.5 Hz,1H), 6.84 (s, 1H), 6.94 (m, 2H). Anal. Calcd. For C₂₈H₃₄N₄O₄: C, 68.55;H, 6.99; N, 11.43. Found: C, 68.42; H, 6.76; N, 11.57.

Step 1:6-Cyclopentyl-6-[2-(4-methoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

6-Cyclopentyl-6-[2-(4-methoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas prepared analogously to Example A(82), where4-Bromo-1-methoxy-2-methyl-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

Example B(10)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-6-[2-(4-ethoxy-3-methyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(4-ethoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Example A(3), to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described in thesynthesis of Example B(31).

¹H NMR (CDCl₃): δ 1.39 (t, J=7 Hz, 3H), 1.52-1.81 (brm, 8H), 2.05 (m,2H), 2.16 (s, 3H), 2.35 (m, 1H), 2.50-2.71 (m, 8H), 2.79 (s, 3H), 3.98(q, J=7 Hz, 2H), 4.05 (d, J=15.5 Hz, 1H), 4.12 (d, J=15.5 Hz, 1H), 6.69(d, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.91 (m, 2H). Anal. Calcd. ForC₂₉H₃₆N₄O₄: C, 69.02; H, 7.19; N, 11.10. Found: C, 69.42; H, 7.34; N,11.22.

Example B(11)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-isopropoxy-3-methyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(4-isopropoxy-3-methyl-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Example A(4), to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described in thesynthesis of Example B(31).

¹H NMR (CDCl₃): δ 1.30 (d, J=6.2 Hz, 6H), 1.52-1.81 (brm, 8H), 1.99 (m,2H), 2.15 (s, 3H), 2.38 (m, 1H), 2.50-2.71 (m, 8H), 2.79 (s, 3H), 4.05(d, J=15.5 Hz, 1H), 4.12 (d, J=15.5 Hz, 1H), 4.43 (m, 1H), 6.71 (d,J=8.1 Hz, 1H), 6.84 (s, 1H), 6.88 (m, 2H). Anal. Calcd. For C₃₀H₃₈N₄O₄:C, 69.47; H, 7.38; N, 10.80. Found: C, 69.18; H, 7.54; N, 10.66.

Example B(12)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione fromStep 1 below to5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described in thesynthesis of Example B(31).

¹H NMR (CDCl₃): δ 1.20 (t, J=7.5 Hz, 3H), 1.52-1.81 (brm, 8H), 2.04 (m,2H), 2.39 (m, 1H), 2.50-2.73 (m, 10H), 2.79 (s, 3H), 4.05 (d, J=15.5 Hz,1H), 4.12 (d, J=15.5 Hz, 1H), 6.84 (s, 1H), 6.98 (m, 3H), 7.17 (t, J=7.6Hz, 1H). Anal. Calcd. For C₂₈H₃₄N₄O₃: C, 70.86; H, 7.22; N, 11.81.Found: C, 70.68; H, 7.06; N, 11.64.

Step 1:6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione wasprepared analogously to Example A(82), where 3-ethyl-bromobenzene wassubstituted in place of 2-Bromopyridine in Step 1 of that example.

Example B(13)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-dihydro-pyran-2,4-dione

6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 below (1 g, 2.90 mmol) was combined with5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (0.5 g,2.90 mmol) (described in Step 3 of example B(75)) in dry THF (15 mL)with magnetic stirring. To this solution was added AlCl₃ (0.76 g, 5.81mmol) as a soln in THF (6 mL) dropwise over 1 min. The resulting yellowsolution was stirred at room temperature for 3 hours. The reaction wasquenched with solid Na₂CO₃.10H₂O (1.63 g, 5.81 mmol) and stirred at roomtemperature for 10 min. Next, the mixture was treated with MgSO₄ (2.5 g)and the slurry allowed to stand for 1.5 hours. The yellow mixture wasfiltered through celite and the filtrate was concentrated. The cruderesidue was dissolved in EtOAc (50 mL) and treated with PtO₂ and stirredwith H₂ (one balloon pressure). This was maintained for 1 hour thenfiltered through celite. The filtrate was concentrated and the residuechromatographed on silica gel eluting with CH₂Cl₂ through 0.75% MeOH inCH₂Cl₂ to yield the title compound as a white solid.

¹H NMR (CDCl₃): δ 1.37-1.85 (brm, 8H), 1.98 (m, 2H), 2.37 (m, 1H),2.49-2.80 (m, 11H), 3.86 (s, 3H), 4.05 (d, J=15.6 Hz, 1H), 4.12 (d,J=15.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 7.00 (d, J=8.6 Hz,1H), 7.12 (s, 1H). Anal. Calcd. For C₂₇H₃₁ClN₄O₄: C, 63.46; H, 6.11; N,10.96. Found: C, 63.23; H, 6.27; N, 10.74.

Step 1:6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas prepared analogously to Example A(82), where4-Bromo-2-chloro-1-methoxy-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

Example B(14)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylmethyl)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 below to5-Chloro-1-isopropyl-1H-benzoimidazole-2-carbaldehyde using theAlCl₃/reduction procedure described in Example B(13).

ESIMS (MH+): 570.3

Step 1:6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas prepared analogously to Example A(82), where4-Bromo-2-fluoro-1-isopropoxy-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

Example B(15) 6-Cyclopentyl-6-[2-(3-fluoro4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(5-methyl-isoxazol-3-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 of Example B(14), to 5-Methyl-isoxazole-3-carbaldehyde usingthe AlCl₃/reduction procedure described for Example B(13).

¹H NMR (CDCl₃): δ 1.32 (d, J=6 Hz, 6H), 1.44-1.92 (brm, 8H), 2.05 (m,2H), 2.44-2.88 (m, 8H), 2.95 (s, 3H), 4.47 (m, 1H), 6.72-6.92 (m, 2H),7.66 (m, 2H). ESIMS (MH+): 458.3.

Example B(16)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 of Example B(14), to1-Methyl-1H-benzoimidazole-2-carbaldehyde using the AlCl₃/reductionprocedure described for Example B(13).

¹H NMR (CDCl₃): δ 1.32 (d, J=6 Hz, 6H), 1.45-1.91 (brm, 8H), 2.05 (m,2H), 2.44-2.88 (m, 8H), 2.91 (s, 3H), 4.48 (m, 1H), 6.75-6.92 (m, 3H)7.22-7.45 (m, 3H) 7.66 (s, 1H). ESIMS (MH+): 507.2.

Example B(17)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(4-methoxy-benzyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 4-Methoxy-benzaldehyde using theAlCl₃/reduction procedure described for Example B(13). ¹H NMR (CDCl₃): δ1.45-1.85 (brm, 8H), 1.98 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44-3.02 (m,7H), 3.88 (s, 3H), 3.94 (s, 3H), 6.73-7.85 (m, 7H). ESIMS (MH+): 471.7.

Example B(18)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionefrom Step 1 of Example B(14), to5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75)) using the Me₂NHBH₃ method described in thesynthesis of Example B(31). ¹H NMR (CDCl₃): δ 1.30 (d, J=6.2 Hz, 6H),1.52-1.81 (brm, 8H), 1.99 (m, 2H), 2.38 (m, 1H), 2.50-2.72 (m, 8H), 2.78(s, 3H), 4.05 (d, J=15.5 Hz, 1H), 4.12 (d, J=15.5 Hz, 1H), 4.45 (m, 1H),6.84 (s, 1H), 6.86-6.93 (m, 3H). Anal. Calcd. For C₂₉H₃₅FN₄O₄: C, 66.65;H, 6.75; N, 10.72. Found: C, 66.28; H, 6.87; N, 10.52.

Example B(19)6-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 below to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75), using the Me₂NHBH₃ method described in thesynthesis of Example B(31). ¹H NMR (CDCl₃): δ 1.44-1.92 (brm, 8H), 2.05(m, 2H), 2.35 (m, 1H) 2.44-2.88 (m, 11H), 4.05 (s, 2H), 6.85 (s, 1H),6.99 (m, 2H) 7.15 (d, J=7.5 Hz, 1H). Anal. Calcd. For C₂₆H₂₈ClFN₄O₃: C,62.58; H, 5.66; N, 11.23. Found: C, 62.42; H, 5.46; N, 11.55.

Step 1:6-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

6-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas prepared analogously to Example A(82), where4-Bromo-2-chloro-1-fluoro-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

Example B(20)6-[2-(3-Chloro-4-ethoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-ethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 below to5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (describedin Step 3 of example B(75), using the Me₂NHBH₃ method described in thesynthesis of Example B(31). ¹H NMR (CDCl₃): δ 1.39 (t, J=7.2 Hz, 3H),1.52-1.82 (brm, 8H), 2.05 (m, 2H), 2.35 (m, 1H), 2.50-2.71 (m, 8H), 2.79(s, 3H), 3.96 (q, J=7.2 Hz, 2H), 4.05 (d, J=15.5 Hz, 1H), 4.12 (d,J=15.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.84 (s, 1H), 6.91 (m, 2H).Anal. Calcd. For C₂₈H₃₃ClN₄O₄: C, 64.05; H, 6.34; N, 10.67. Found: C,64.40; H, 6.26; N, 10.88.

Step 1:6-[2-(3-Chloro-4-ethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

6-[2-(3-Chloro-4-ethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas prepared analogously to Example A(82), where4-Bromo-2-chloro-1-ethoxy-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

Example B(21)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(4-methanesulfonyl-benzyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 4-Methanesulfonyl-benzaldehyde usingthe Me₂NHBH₃ method described in the synthesis of Example B(31). ¹H NMR(CDCl₃): δ 1.45-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H)2.44-3.02 (m, 7H), 3.91 (s, 3H), 3.94 (s, 3H), 6.88-7.85 (m, 7H).

Example B(22)4-{6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2-pyran-3-ylmethyl}-benzonitrile

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 4-Formyl-benzonitrile using theMe₂NHBH₃ method described in the synthesis of Example B(31).¹HNMR(CDCl₃): δ 1.45-1.86 (brm, 8H), 2.02 (m, 2H), 2.29 (m, 1H)2.44-3.02 (m, 7H), 3.94 (s, 3H), 6.88-7.85 (m, 7H). Anal. Calcd. ForC₂₇H₂₈ClNO₄: C, 69.59; H, 6.06; N, 3.01. Found: C, 69.40; H, 6.22; N,3.07.

Example B(23)3-{6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2-pyran-3-ylmethyl}-benzonitrile

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 3-Formyl-benzonitrile using theMe₂NHBH₃ method described in the synthesis of Example B(31). ¹H NMR(CDCl₃): δ 1.43-1.86 (brm, 8H), 2.02 (m, 2H), 2.29 (m, 1H) 2.44-3.02 (m,7H), 3.95 (s, 3H), 6.88-7.91 (m, 7H). Anal. Calcd. For C₂₇H₂₈ClNO₄: C,69.59; H, 6.06; N, 3.01. Found: C, 69.67; H, 6.14; N, 3.13.

Example B(24)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(4-pyrazol-1-yl-benzyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 4-Pyrazol-1-yl-benzaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).ESIMS (MH+):508.1.

Example B(25)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(4-[1,2,4]triazol-1-yl-benzyl)-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionefrom Step 1 of Example B(13), to 4-[1,2,4]Triazol-1-yl-benzaldehydeusing the Me₂NHBH₃ method described in the synthesis of ExampleB(31).ESIMS (MH+): 509.1.

Example B(26)6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31),carbaldehyde where6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneand 1-methyl-2-formylbenzimidazole was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): δ 0.10 (d, J=4.7, 2H), 0.33-0.36 (m, 2H), 0.98-2.04(m, 14H), 2.17-2.26 (m, 2H), 2.29 (d, J=17, 1H), 2.54 (d, J=17 Hz, 1H),3.56 (s, 3H), 3.60-3.65 (m, 2H), 3.85 (brs, 1H), 6.71-7.26 (m, 7H).Anal. Calcd. For C₃₁H₃₅ClN₂O₄.0.5H₂O: C, 68.43, H, 6.67, N, 5.15. Found:C, 68.36, H, 6.58, N, 4.81. ESIMS (MH+): 536.

Example B(27)6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where1-methyl-2-formylbenzimidazole was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): 60.90-1.36 (m, 14H), 1.54-1.61 (m, 2H), 2.20-2.39 (m,3H), 2.57-2.73 (m, 4H), 4.10 (s, 3H), 4.44-4.49 (m, 1H), 6.49-6.48 (m,7H), 13.5 (brs, 1H); Anal. Calcd. For C₃₀H₃₅ClN₄O₄: C, 68.89, H, 6.74,N, 5.36. Found: C, 69.11, H, 6.73, N, 5.36. ESIMS (MH+): 524.

Example B(28)6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 0.35-0.38 (m, 2H), 0.61-0.64 (m, 2H), 1.26-1.85 (m,8H), 1.94-2.05 (m, 1H), 2.18 (s, 2H), 2.37-2.79 (m, 12H), 3.83 (d, J=6.8Hz, 2H), 4.09 (s, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.1, 2.2 Hz,1H), 7.11 (d, J=2.2 Hz, 1H), 7.26 (s, 1H), 14.1 (brs, 1H). Anal. Calcd.For C₃₀H₃₅ClN₄O₄.0.2 AcOH: C, 64.84, H, 6.41, N, 9.95. Found: C, 64.82,H, 6.42, N, 9.69. ESIMS (MH+): 552.

Example B(29)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-3-(4-chloro-1-methyl-1H-pyrazol-3-ylmethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneand 4-chloro-1-methyl-1H-pyrazole-3-carbalehyde was substituted in placeof 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): δ 1.50-1.71 (m, 8H), 2.01-2.05 (m, 2H), 2.39-2.41 (m,1H), 2.49-2.57 (m, 2H), 2.74 (d, J=16 Hz, 1H), 3.18 (d, J=5.3 Hz, 1H),3.39 (d, J=16.0 Hz, 1H), 3.47 (d, J=16 Hz, 1H), 3.60 (s, 3H), 3.83 (s,3H), 7.05 (d, J=8.3 Hz, 1H), 7.11 (dd, J=8.3. 2.0 Hz, 1H), 7.23 (d,J=2.0 Hz, 1H), 7.76 (s, 1H), 10.64 (s, 1H). Anal. Calcd. ForC₂₄H₂₈Cl₂N₂O₄: C, 60.13, H, 5.89, N, 5.84. Found: C, 59.94, H, 5.95, N,5.69. ESIMS (MH+): 480.

Example B(30)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(1H-imidazol-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneand imidazole-2-carboxaldehyde was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): δ 1.05-1.55 (m, 8H), 1.79-1.83 (m, 2H), 2.21-2.29 (m,2H), 2.42-2.45 (m, 2H), 2.62-2.76 (m, 3H), 3.70 (s, 3H), 4.64 (s, 1H),6.93 (d, J=8.3 Hz, 1H), 6.99-7.02 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.39(s, H), 7.48 (s, 1H), 11.76 (brs, 1H). ESIMS (MH+): 431.

Example B(31)6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(0.3 g, 0.79 mmol) and5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.17 g,0.95 mmol, described in Step 3 of example B(75)) were dissolved in 3:1MeOH/CH₂Cl₂ (4 mL). To this suspension, Me₂NH.BH₃ (0.07 g, 1.19 mmol)was added as a solid from top. After stirring 1 h at room temperature,the reaction mixture became clear and it was stirred for an additional 5hours. After this time, 1 M HCl (1 mL) was added and the reactionstirred for 30 minutes at room temperature, the solvent was theevaporated to half the volumen and extracted 3 times with 10%MeOH/CH₂Cl₂ (10 mL). The organic phase was dried over MgSO₄ andevaporated. The residue purified by flash column chromatography (80%EtOAc in hexanes) to eliminate unreacted pyrone and reduced5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde, then 3%MeOH/CH₂Cl₂ to give the product (0.1 g, 24%) as a white solid.

¹H NMR (DMSO-d₆): δ 1.14 (d, J=6.3, 6H), 1.4-1.53 (m, 8H), 1.7-1.75 (m,2H), 1.95-1.98 (m, 1H), 2.35-2.44 (m, 8H), 3.19 (s, 2H), 3.57 (d, J=16Hz, 1H), 3.69 (d, J=16 Hz, 1H), 4.41-4.47 (m, 1H), 6.91-6.93 (s, 1H),7-7.07 (m, 2H), 7.10 (d, J=2.0, 1H), 10.7 (brs, 1H). Anal. Calcd. ForC₂₉H₃₅N₄O₄: C, 64.61, H, 6.54, N, 10.39. Found: C, 64.30, H, 6.81, N,10.35. ESIMS (MH+): 540.

Example B(32)6-[2-(5-Chloro-2,4-dimethoxy-phenyl)-ethyl]-3-(4-chloro-1-methyl-1H-pyrazol-3-ylmethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-[2-(5-Chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(described in Step 1 of example B(35)) was substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneand 4-chloro-1-methyl-1H-pyrazole-3-carbalehyde was substituted in placeof 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): δ 1.35-1.70 (m, 8H), 1.90-1.99 (m, 2H), 2.33-2.38 (m,1H), 2.39-2.53 (m, 3H), 2.72 (d, J=17 Hz, 1H), 3.34-3.47 (m, 2H), 3.57(s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 6.73 (s, 1H), 7.07 (s, 1H), 7.73(s, 1H), 10.61 (s, 1H). Anal. Calcd. For C₂₅H₃₀Cl₂N₂O₅: C, 58.94, H,5.94, N, 5.50. Found: C, 58.78, H, 6.02, N, 5.39. ESIMS (MH+): 510.

Example B(33)6-Cyclopentyl-6-[2-(4-cyclopropylmethoxy-3-fluoro-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(4-cyclopropylmethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione(prepared in Step 2 below) was substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 0.09-0.11 (m, 2H), 0.32-0.39 (m, 2H), 0.98-1.48 (m,8H), 1.84-1.90 (m, 2H), 2.16-2.22 (m, 1H), 2.28-2.33 (m, 10H), 2.56 (d,J=16 Hz, 1H), 3.47-3.63 (m, 4H), 6.76-6.86 (m, 4H), 10.65 (brs, 1H).Anal. Calcd. For C₃₀H₃₅FN₄O₄.0.25H₂O: C, 66.84, H, 6.64, N, 10.39.Found: C, 67.07, H, 6.74, N, 10.05. ESIMS (MH+): 535.

Step 1: 4-Bromo-1-cyclopropylmethoxy-2-fluoro-benzene

The title compound was prepared analogously to Step 1 in Example A(52),where (bromomethyl)-cyclopropane was substituted instead of methylα-bromobutyrate of that example.

¹H NMR (CDCl₃) δ 0.32-0.42 (m, 2H), 0.62-0.68 (m, 2H), 1.23-1.33 (m,1H), 3.85 (d, J=6.9 Hz, 2H), 6.82 (t, J=8.8 Hz, 1H), 7.14-7.18 (m, 1H),7.23 (dd, J=10.5, 2.3 Hz, 1H). ESIMS (MH+): 246.1.

Step 26-Cyclopentyl-6-[2-(4-cyclopropylmethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where4-Bromo-1-cyclopropylmethoxy-2-fluoro-benzene from Step 1 below wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

¹H NMR (CDCl₃-d₆): δ 0.32-0.37 (m, 2H), 0.61-0.67 (m, 2H), 1.26-1.30 (m,1H), 1.57-1.84 (m, 8H), 1.89-1.96 (m, 2H), 2.26 (t, J=8.4 Hz, 1H), 2.61(t, J=8.4 Hz, 2H), 2.75 (s, 2H), 3.42 (s, 2H), 3.84 (d, J=6.9 Hz, 2H),6.78-6.89 (m, 3H). Anal. Calcd. For C₂₂H₂₇FO₄: C, 70.57; H, 7.27. Found:C, 70.63; H, 7.40.

ESIMS (MNa+): 397.1.

Example B(34)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a!pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-isopropoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 1.39 (d, J=6.1, 6H), 1.43-1.86 (m, 8H), 2.22-2.28(m, 2H), 2.54-2.57 (m, 1H), 2.57-2.70 (m, 9H), 2.94 (d, J=17 Hz, 1H),3.86 (d, J=16 Hz, 1H), 3.97 (d, J=16 Hz, 1H), 4.65-4.71 (m, 1H), 6.93(d, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.27 (d, J=8.6, 2H), 10.99 (s, 1H).Anal. Calcd. For C₂₉H₃₆N₄O₄.0.25H₂O: C, 68.41, H, 7.23, N, 11.00 Found:C, 68.40, H, 7.23, N, 10.99. ESIMS (MH+): 505.

Step 1:6-Cyclopentyl-6-[2-(4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where1-Bromo-4-isopropoxy-benzene was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃-d₆): δ 1.32 (d, J=6.2 Hz, 6H), 1.58-1.7 (m, 8H), 1.89-1.99(m, 1H), 2.2-2.31 (m, 2H), 2.61 (t, J=8.6 Hz, 2H), 2.77 (s, 2H), 3.43(s, 2H), 4.52 (septet, J=12, 6 Hz, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.03 (d,J=8.5 Hz, 2H). Anal. Calcd. For C₂₁H₂₈O₄: C, 73.23; H, 8.19. Found: C,73.43; H, 8.44. ESIMS (MH+): 345.2.

Example B(35)6-[2-(5-Chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(2-methyl-1H-imidazol-4-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-[2-(5-Chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(described below), as substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneand 2-methyl-1H-imidazole-4-carbaldehyde was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample.

¹H NMR (DMSO-d₆): δ 1.08-1.58 (m, 10H), 2.02-2.42 (m, 9H), 3.20-3.22 (m,2H), 3.53 (s, 3H), 3.61 (s, 3H), 6.47 (s, 1H), 6.53 (s, 1H), 6.86 (s,1H), 10.9 (s, 1H). Anal. Calcd. For C₂₅H₃₁ClN₂O₅.1.5H₂O: C, 59.82, H,6.83, N, 5.58. Found: C, 59.87, H, 6.58, N, 5.46. ESIMS (MH+): 475.

Step 1.6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

A solution of6-[2-(2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(from example A(39); 4.50 g, 13 mmol) in CH₂Cl₂ (20 mL) was cooled to−5° C. and treated with a solution of SO₂Cl₂ (1.94 g, 14.3 mmol) inCH₂Cl₂ (10 mL) dropwise under nitrogen. The reaction mixture was stirredfor an additional 15 minutes at −5° C., then allowed to warm graduallyto room temperature. After a total reaction time of 2 h, an aqueoussolution of NaHCO₃ (5 wt %) was added to achieve a pH of 8 in theaqueous phase. The volatiles were removed in vacuo. The residue wastreated with water and extracted with ethyl acetate (3×25 mL). Thecombined ethyl acetate extract was acidified to a pH 2 using 2 N HCl,then washed with water. The organic phase was dried over Na₂SO₄,filtered, and concentrated to a yellowish solid. Recrystallization fromether afforded the title product as a white solid (2.18 g, 44%).

¹H NMR (CDCl₃) δ 1.74 (m, 8H), 2.32 (m, 1H), 2.58 (m, 2H), 2.78 (s, 2H),3.43 (s, 2H), 3.82 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 7.07 (s, 1H).HRMS calcd for C₂₀H₂₅O₅Cl (M+H⁺): 381.1469, found 381.1475.

Example B(36)6-Cyclopentyl-6-[2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-dihydro-pyran-2,4-dione(from Step 1 below) was substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 1.31-1.55 (m, 8H), 1.82-1.91 (m, 2H), 2.20-2.22 (m,1H), 2.33-2.63 (m, 10H), 3.54 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H),4.01 (s, 4H), 6.47-6.57 (m, 3H), 6.88 (s, 1H), 10.65 (s, 1H). Anal.Calcd. For C₂₈H₃₂N₄O₅: C, 66.65, H, 6.39, N, 11.10 Found: C, 66.80, H,6.75, N, 11.38. ESIMS (MH+): 505.

Step 16-Cyclopentyl-6-[2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where1-Bromo-1,2-(ethylene-dioxy)benzene was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

¹H NMR (CDCl₃-d₆): δ 1.5-1.6 (m, 8H), 1.71-1.97 (m, 2H), 2.2-2.3 (m,1H), 2.57 (t, J=8.5 Hz, 2H), 2.76 (s, 2H), 3.42 (s, 2H), 4.24 (s, 4H),6.59-6.85 (m, 2H), 6.78 (d, J=8.3 Hz, 1H). Anal. Calcd. For C₂₀H₂₄O₅: C,69.75; H, 7.02. Found: C, 69.83; H, 7.31. ESIMS (MH+): 345.2.

Example B(37)6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(from Step 2 below) was substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 1.53 (t, J=6.9, 3H), 1.59-1.9 (m, 8H), 2.26-2.32 (m,2H), 2.67-2.98 (m, 11H), 3.89 (d, J=16 Hz, 1H), 4.0 (d, J=16 Hz, 1H),4.17 (q, J=6.9 Hz, 2H), 7.23 (s, 1H), 7.51 (s, 2H), 11.01 (s, 1H). Anal.Calcd. For C₂₈H₃₂Cl₂N₄O₄.0.75H₂O: C, 58.60, H, 5.64, N, 9.59 Found: C,58.60, H, 5.64, N, 9.59. ESIMS (MH+): 560.

Step 1: 4-Bromo-1-cyclopropylmethoxy-2-fluoro-benzene

The title compound was prepared analogously to Step 1 in Example A(52),where iodoethane was substituted instead of methyl α-bromobutyrate and4-Bromo-2,6-dichloro-phenol was substituted instead of4-Bromo-2-fluorophenol of that example.

¹H NMR (CDCl₃) δ 0.32-0.42 (m, 2H), 0.62-0.68 (m, 2H), 1.23-1.33 (m,1H), 3.85 (d, J=6.9 Hz, 2H), 6.82 (t, J=8.8 Hz, 1H), 7.14-7.18 (m, 1H),7.23 (dd, J=10.5, 2.3 Hz, 1H). ESIMS (MH+): 246.1.

Step 2:6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where5-Bromo-1,3-dichloro-2-ethoxy-benzene (from Step 1 above) wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

Example B(38)6-Cyclopentyl-6-[2-(3,4-dichloro-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(3,4-dichloro-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 1.5-2.0 (m, 8H), 2.18-2.24 (m, 2H), 2.45-2.54 (m,1H), 2.60-2.93 (m, 10H), 3.81 (d, J=16 Hz, 1H), 3.93 (d, J=16 Hz, 1H),7.15 (s, 1H), 7.42 (dd, J=8.2, 2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.62(d, J=8.2 Hz, 1H), 10.94 (s, 1H). Anal. Calcd. For C₂₆H₂₈Cl₂N₄O₃: C,60.59, H, 5.48, N, 10.87; Found: C, 60.71, H, 5.79, N, 10.98. ESIMS(MH+): 516.

Step 1:6-Cyclopentyl-6-[2-(3,4-dichloro-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where4-Bromo-1,2-dichloro-benzene was substituted in place of1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3 of that example.

Example B(39)6-(4-Cyclohexyl-butyl)-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-α]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-(4-Cyclohexyl-butyl)-6-cyclopentyl-dihydro-pyran-2,4-dione wassubstituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 0.76-1.93 (m, 25H), 2.27-2.32 (m, 1H), 2.50-2.75 (m,10H), 3.69 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 7.08 (s, 1H), 10.77(s, 1H). Anal. Calcd. For C₂₈H₄₀N₄O₃.0.5 CH₃OH: C, 68.92, H, 8.39, N,11.28; Found: C, 69.24, H, 8.34, N, 11.00. ESIMS (MH+): 481.

Example B(40)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-dihydro-pyran-2,4-dione(prepared in Step 1 below) was substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 0.98-1.68 (m, 8H), 1.93-2.02 (m, 2H), 2.27-2.68 (m,11H), 3.56 (d, J=16 Hz, 1H), 3.68 (d, J=16 Hz, 1H), 6.90 (s, 1H), 7.12(dd, J=8.5, 1.8 Hz, 1H), 7.19 (s, 1H), 7.22 (d, J=1.8 Hz, 1H), 10.69 (s,1H). Anal. Calcd. For C₂₈H₂₈F₄N₄O₅.0.5H₂O: C, 57.43, H, 4.99, N, 9.57;Found: C, 57.42, H, 4.89, N, 9.65. ESIMS (MH+): 577.

Step 1:6-Cyclopentyl-6-[2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(27), where6-Bromo-2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxine wassubstituted in place of 1-(4-Bromo-2-chloro-phenyl)-ethanone in Step 3of that example.

Example B(41)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-propoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-[2-(4-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione wassubstituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): δ 0.79 (t, J=7.4, 3H), 1.20-1.57 (m, 10H), 1.85-1.96(m, 2H), 2.20-2.44 (m, 10H), 2.61 (d, J=16 Hz, 1H), 3.53 (d, J=16 Hz,1H), 3.63-3.72 (m, 3H), 6.62 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 6.95 (d,J=8.4, 2H), 10.65 (s, 1H). Anal. Calcd. For C₂₉H₃₆N₄O₄: C, 69.02, H,7.19, N, 11.10 Found: C, 69.25, H, 7.40, N, 10.92. ESIMS (MH+): 505.

Example B(42)6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-phenyl]-ethyl}-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione6-Cyclopentyl-6-(2-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}ethyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-onewas substituted in place of6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (DMSO-d₆): 1.36-1.71 (m, 8H), 2.08-2.09 (m, 2H), 2.22 (s, 3H),2.40 (s, 3H), 2.48-2.56 (m, 10H), 2.77 (d, J=16 Hz, 1H), 3.70 (d, J=16Hz, 1H), 3.82 (d, J=16 Hz, 1H), 4.88 (s, 2H), 6.90 (d, J=8.2 Hz, 2H),7.04 (s, 1H), 7.17 (d, J=8.2, 2H), 10.69 (s, 1H). Anal. Calcd. ForC₃₂H₃₇N₅O₅: C, 67.23, H, 6.52, N, 12.25 Found: C, 67.36, H, 6.80, N,12.45. ESIMS (MH+): 572.

Example B(43)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)methyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(3-fluoro-4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentydihydro-2H-pyran-2,4(3H)-dioneand 5-chloro-1-methyl-1H-benzimidazole-2-carbaldehyde was substituted inplace of 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde.

¹H NMR (300 MHz, CDCl₃) δ: 1.51-1.75 (m, 8H), 1.96-2.02 (m, 2H),2.51-2.58 (m, 2H), 2.70-2.82 (m, 3H), 3.86 (s, 3H), 3.87 (s, 2H), 3.89(s, 3H), 6.82 (t, J=8.01 Hz, 1H), 6.96-7.05 (m, 1H), 7.14-7.19 (m, 1H),7.25-7.28 (m, 2H), 7.64 (s, 1H). HRMS calcd for C₂₈H₃₁Cl₂N₂O₄ (M+H⁺):529.1656. Found: 529.1637.

Example B(44)6-[2-(3-chloro-4-isopropylphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(3-chloro-4-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (d, J=6.78 Hz, 6H), 1.47-1.74 (m, 8H),1.96-2.02 (m, 2H), 2.32-2.40 (m, 1H), 2.50-2.61 (m, 3H), 2.66 (s, 3H),2.71-2.73 (m, 1H), 2.79 (s, 3H), 3.29-3.38 (m, 1H), 4.09 (s, 2H), 6.84(s, 1H), 7.00 (dd, J=7.91, 1.51 Hz, 1H), 7.10 (s, 1H), 7.16 (d, J=7.91Hz, 1H). HRMS calcd for C₂₉H₃₆ClN₄O₃ (M+H⁺): 523.2471. Found: 523.2465.

Example B(45)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropylphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(3-fluoro-4-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.

¹H NMR (CDCl₃, 300 MHz) δ: 1.21 (d, J=6.97 Hz, 6H), 1.24-1.26 (m, 2H),1.46-1.76 (m, 6H), 1.97-2.03 (m, 2H), 2.35-2.41 (m, 1H), 2.48-2.54 (m,1H), 2.61-2.65 (m, 2H), 2.67 (s, 3H), 2.70-2.73 (m, 1H), 2.79 (s, 3H),3.12-3.20 (m, 1H), 4.03-4.15 (m, 2H), 6.76 (dd, J=11.49, 1.51 Hz, 1H),6.85 (s, 1H), 6.88 (d, J=1.51 Hz, 1H), 7.11 (t, J=7.91 Hz, 1H). HRMScalcd for C₂₉H₃₆FN₄O₃ (M+H⁺): 507.2766. Found: 507.2751.

Example B(46)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-fluorophenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(3-ethyl-4-fluorophenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein the final Step of that example.

¹H NMR (CDCl₃): δ 0.80 (m, 2H), 1.06 (m, 2H), 1.19 (t, J=7.63 Hz, 3H),1.45-1.80 (brm, 8H), 2.06 (m, 2H), 2.45 (m, 2H), 2.65 (m, 2H), 2.70 (s,3H), 2.80 (s, 3H), 4.13 (d, J=5.09 Hz, 2H), 6.74 (m, 1H), 6.80 (m, 2H),7.15 (m, 1H). Anal. Calcd. For C₂₈H₃₃O₃N₄F: C, 68.27; H, 6.75, N, 11.37.Found: C, 68.14; H, 6.46, N, 11.53.

Example B(47)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(1,3-thiazol-2-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where1,3-thiazole-2-carbaldehyde was substituted in place of5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein final Step of that example.

¹H NMR (CDCl₃): δ 1.44-1.70 (bm, 8H), 2.0 (m, 2H), 2.40 (m, 1H), 2.60(m, 3H), 2.76 (d, J=17.90 Hz, 1H), 3.88 (s. 3H), 4.56 (d, J=15.07 Hz,1H), 4.76 (d, J=15.07 Hz, 1H), 6.70 (d, J=2.07 Hz, 1H), 6.98, (d, J=2.07Hz, 1H), 7.11 (s, 1H), 7.63, (d, J=3.96 Hz, 1H), 7.87 (d, J=3.96 Hz,1H). Anal. Calcd. For C₂₄H₂₈O₃SNCl: C, 64.63; H, 6.33, N, 3.14. Found:C, 64.55; H, 6.64, N, 3.10.

Example B(48)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-methyl-1H-imidazol-2-yl)methyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where1-methyl-1H-imidazole-2-carbaldehyde was substituted in place of5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein that example.

¹H NMR (CDCl₃): δ 1.44-1.70 (bm, 8H), 2.0 (m, 2H), 2.20 (m, 3H), 2.30(m, 2H), 2.99 (m, 2H), 3.01 (M. 2H), 3.46 (s, 3H) 3.78 (m, 1H), 3.89 (s,3H), 6.72 (d, J=2.15 Hz, 1H), 6.83, (d, J=2.15 Hz, 1H), 6,90 (s, 1H),7.14, (d, J=3.07 Hz, 1H), 7.24 (d, J=3.06 Hz, 1H). Anal. Calcd. ForC₂₅H₃₁O₃N₂Cl: C, 67.78; H, 7.05, N, 6.32. Found: C, 67.48; H, 7.25, N,6.37.

Example B(49) 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(3-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(described below) was substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein that example.

¹H NMR (CDCl₃): δ 0.88 (m, 1H), 1.21 (d, J=6.78 Hz, 6H), 1.26 (s, 2H),1.48-1.77 (brm, 8H), 2.04 (m, 2H), 2.41 (m, 1H), 2.52-2.58 (m, 2H), 2.67(s, 3H), 2.79 (s, 3H), 2.87 (m, 2H) 4.09 (s, 2H), 6.84 (s, 1H), 6.98 (d,J=7.54 Hz, 1H), 7.00 (m, 2H), 7.18 (t, J=7.54 Hz 1H). Anal. Calcd. ForC₂₉H₃₆O₃N₄: C, 71.28; H, 7.43, N, 11.47. Found: C, 71.51; H, 7.25, N,11.37.

Step 1:6-Cyclopentyl-6-[2-(3-isopropyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example A(64), where3-bromo-isopropyl-benzene was substituted in place of4-Bromo-2-fluoro-1-isopropyl benzene in Step 3 of that example.

¹H NMR (CDCl₃): ? 1.24 (d, 6H, J=8.5 Hz)1.40-1.75 (m, 4H), 1.99 (m, 2H),2.29 (pentet, 1H, J=8.1 Hz), 2.66 (t, 2H, J=8.5 Hz), 2.78 (s, 2H), 2.87(m, 1H), 3.42 (s, 3H), 6.97 (m, 2H), 7.10 (m, 1H), 7.22 (m, 1H). Anal.Calcd. For C₂₁H₂₈O₃.0.25H₂O: C, 75.75; H, 8.63. Found: C, 75.68; H,8.48. ESIMS (M−H⁻¹): 327.2.

Example B(50) 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(4-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where6-cyclopentyl-6-[2-(4-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein that example.

¹H NMR (CDCl₃): δ 0.98 (m, 1H), 1.24 (d, J=6.78 Hz, 6H), 1.31 (s, 2H),1.40-1.77 (brm, 8H), 2.06 (m, 2H), 2.41 (m, 1H), 2.50-2.59 (m, 2H), 2.68(s, 3H), 2.79 (s, 3H), 2.95 (m, 2H) 4.25 (s, 2H), 6.90 (s, 1H), 7.15 (d,J=8.10 Hz, 1H), 7.30 (d, J=8.10 Hz 1H), Anal. Calcd. For C₂₉H₃₆O₃N₄: C,71.28; H, 7.43, N, 11.47. Found: C, 71.35; H, 7.55, N, 11.47.

Example B(51)6-[2-(3-chlorophenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(31), where6-[2-(3-chlorophenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein that example.

¹H NMR (CDCl₃): δ 1.30 (m, 1H), 1.40-1.80 (brm, 8H), 2.10 (m, 2H), 2.41(m, 1H), 2.52-2.58 (m, 2H), 2.67 (s, 3H), 2.80 (s, 3H), 2.87 (m, 2H)4.09 (s, 2H), 6.84 (s, 1H), 6.98 (d, J=6.25 Hz, 1H), 7.20 (t, J=8.35 Hz2H), 7.30 (m, 1H) Anal. Calcd. For C₂₆H₂₉O₃N₄Cl: C, 64.92; H, 6.08, N,11.65. Found: C, 65.14; H, 6.25, N, 11.73.

Example B(52)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared by treating a suspension of6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(350 mg, 0.917 mmol) and5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxaldehyde (describedin Step 3 of example B(75))(242 mg, 1.375 mmol, 1.5 equiv, from Step 3of Example B(75)) in MeOH (10 mL) with dimethylamine borane (65 mg, 1.1mmol, 1.2 equiv). The resulting mixture was stirred at room temperaturefor 18 h. A 1 M solution of HCl (3 mL) was added to the reaction mixtureto acidify to a pH of 3. The mixture diluted with water and extractedwith dichloromethane containing 10% methanol (3×10 mL). The organiclayers were combined, dried over Na₂SO₄, filtered and concentrated to awhite amorphous foam. The foam was chromatographed on silica gel,eluting with 2% methanol in dichloromethane affording a white solid.This solid was recrystallized from ethyl acetate/hexanes to give 100 mg(19%) of the product as a fine white powder. Isolated as a monohydrate.

¹H NMR d (300 MHz, CDCl₃) 1.58-1.76 (m, 8H), 1.94-1.99 (m, 2H),2.38-2.43 (m, 1H), 2.57-2.77 (m, 2H), 2.69 (s, 3H), 2.81 (s, 3H), 3.82,(s, 3H), 3.85-3.92 (m, 2H), 3.80 (s, 3H), 4.08 (ABQ pattern, 2H, J=15Hz), 6.45 (s, 1H), 6.89 (s, 1H), 7.04 (s, 1H). MS calcd forC₂₈H₃₃ClN₄O₅: 540.05, found (M+H⁺): 541.04. Anal. Calcd forC₂₈H₃₃ClN₄O₅H₂O: C, 60.19; H, 6.32; N, 10.03. Found C, 60.76; H, 5.98;N, 9.54.

Step 1: (5-Amino-1H-1,2,4-triazol-3-yl)methanol Glycolate

The title compound was prepared by a slight modification of a reportedprocedure (Allen, C. F. H. J. Org. Chem, 1959, 24, 793): A 5-L 3-neckedflask was charged with aminoguanidine bicarbonate (275.6 g, 2.025 mol)and octyl alcohol (5.5 mL, to control foaming). To the mixture was added70% aqueous glycolic acid (440 g, 4.05 mol, 2 equiv) gradually, duringwhich time evolution of CO₂ was observed. When foaming and gas evolutionhad ceased, concentrated nitric acid (2.2 mL) was added so that it wetthe sides of the flask above the liquid. The reaction mixture wasrefluxed for 40 h, then cooled to 5° C. and maintained at thistemperature for 40 min. The resulting slurry was filtered, and the solidwashed with EtOH and dried in vacuo at 30° C. to give the crude productas a white solid (313 g). The mother liquor was stirred at 0° C. (icebath) for 1 h and filtered, affording a second batch of material (51 g).These two batches were combined and recrystallized from hot EtOH,affording 271.5 g, (70.5%).

¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (2H), 4.24 (2H), 5.58 (2H). LC-MS(APCI) calcd for C₃H₆N₄O: 114.05; found (M+H⁺): 115.1 m/z.

Step 2: (5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol

The title compound was prepared by a slight modification of a reportedprocedure (Lippman, E.; Becker, V., Z. Chem., 1974, 14, 405): A solutionof (5-amino-1H-1,2,4-triazol-3-yl)methanol glycolate (30.7 g, 0.161 mol,from Step 1, above) and 2,4-pentadione (32.3 g, 0.323 mol, 2 equiv) in amixture of EtOH (750 mL) and AcOH (250 mL) was refluxed 20 h. At thebeginning the reaction mixture was clear solution, then gradually turnedyellow towards the end of the heating period. The solvent was removedunder reduced pressure, and the resulting yellow paste triturated withEtOH (100 mL) and stirred for 15 min. The slurry was chilled to 5° C.(ice bath) with stirring for 30 min, filtered, and washed with cold(0-5° C.) EtOH. The product was dried in vacuo at 25-30° C. to give 24 g(83.7%).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H), 2.71 (3H), 4.63 (2H), 5.5 (1H,OH), 7.13 (1H). LC-MS (APCI) calcd for C₈H₁₀N₄O: 178.19; found (M+H⁺):179.1 m/z.

Example B(53)6-[2-(Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

A suspension of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(140 mg, 0.4 mmol) in 1:1H₂O/DME (4 mL) was treated sequentially with a0.5 M aqueous solution of Na₂CO₃ (0.88 mL, 1.1 equiv), a 0.5 M aqueoussolution of NaI (0.88 mL, 1.1 equiv), and a 0.1 M solution of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole in 1:1H₂O/DME (4.4 mL,1.1 equiv, from Step 1, below). The reaction mixture was stirred andheated at 80° C. for 18 h. The mixture was then cooled and treated with0.4 mL (1 equiv) each of a 1 M HCl solution and a 1 M acetic acidsolution in water. The volatiles were removed in vacuo, and the residuewas dissolved in DMSO to a concentration of 0.01 M. The product waspurified by HPLC in multiple injections using a Pecke Hi-Q 5 μm, 20×100mm column with a 5-90% CH₃CN/0.05% TFA gradient. A run time of 8.1 min,a flow rate of 30.0 mL/min, and a monitoring wavelength of 260 nm wereused. The product-containing fractions were combined and lyophilized,affording the product as a powder. Yield: 11%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.2-1.68 (m, 8H), 2.13 (s, 3H), 2.29 (m,1H), 2.4-2.53 (m, 5H, overlap with DMSO-d₅), 2.70 (d, J=18 Hz, 1H), 3.62(m, 2H, overlap with H₂O), 3.72 (s, 3H), 3.74 (s, 3H), 6.96 (d, J=8.4Hz, 1H), 7.04 (dd, J=8.4, 1.8 Hz, 1H), 7.18 (d, J=1.8 Hz, 1H). LC-MScalcd for C₂₄H₃₀ClN₃O₄: 459.19, found (M+H⁺): 460.1 m/z.

Step 1. 5-(Chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole

The title compound was prepared by a modification of a reported method(Kuebel, B. DE 3118258, Dec. 2, 1982): A 2 L-round bottomed flaskequipped with a magnetic stirrer was charged with acetamidinehydrochloride (94.5 g, 1.0 mol) and methanol (500 mL). Methylhydrazine(50.0 g, 1.1 mol) was added slowly via a dropping funnel over 30 min atroom temperature under nitrogen blanket. After 2 d, the solvent wasremoved in vacuo, and the resulting residue triturated with ethylacetate, filtered, and washed with ethyl acetate (3×400 mL). Afterdrying the residue in a vacuum oven at 50° C., the crude intermediateamidrazone, N′-methylethanehydrazonamide hydrochloride (109.8 g) wasused directly in the next step. This intermediate (109.8 g) wassuspended in dichloromethane (400 mL), cooled to 0-5° C., and treatedslowly with triethylamine (100.2 g) at this temperature. Chloroacetylchloride (103.7 g, 1.02 mol) was added slowly over 30 min at 0-5° C. viaa dropping funnel. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 h under nitrogen blanket. The solvent wasthen removed under reduced pressure, affording a residue (432.6 g)containing the N-chloroacetyl amidrazone intermediate. Polyphosphoricacid, PPA (400 g) was added to this material in a 2 L-3 necked flask,which was equipped with an overhead stirrer, a water condenser and athermometer. The reaction mixture was stirred and heated at 120-130° C.for 4 h. Upon cooling to 80° C., water (400 mL) was added slowly andstirring continued for an additional 2 h. Aqueous NaOH (100 g/l 50 mL)was used to adjust the pH from 3 to 9. The organic material wasextracted with chloroform (4×1 L), and the resulting solution treatedwith activated charcoal, dried with Na₂SO₄, filtered, and evaporatedcarefully. The dark oily residue thus obtained was extracted with amixture of ether (700 mL) and pentane (300 mL) to separate the productfrom insoluble impurities. The yellow supernatant was decanted and thesolvent removed carefully in vacuo (30° C. and ˜10 Torr), affording 60.0g (46% overall) of the title product as an oil (95% pure by NMR).

¹H NMR (300 MHz, CDCl₃) δ 2.35 (s, 3H, C—CH₃), 3.87 (s, 3H, N—CH₃), and4.62 (s, 2H, CH₂). ¹³C NMR (300 MHz, CDCl₃) δ 14.05 (C—CH₃), 34.37(CH₂), 35.81 (N—CH₃), 151.20 (q-C) and 60.22 (q-C). An NOE between CH₂and the N—CH₃ was observed, consistent with the reported regioisomer.LC-MS (APCI) calcd for C₅H₈ClN₃: 145.04; found (M+H⁺) 146.1 m/z (withchorine isotope pattern).

Example B(54)2-([6-[-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-6-methylpyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53) employing2-(chloromethyl)-6-methylpyrimidin-4(3)-one in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole. Yield: 26%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.65 (m, 8H), 1.88 (s, 3H), 1.9-2.1 (m,2H), 2.35 (m, 1H), 2.4-2.54 (m, 3H, overlap with DMSO-d₅), 2.66 (d, J=18Hz, 1H), 3.45 (ABQ, J=15 Hz, 2H), 3.74 (s, 3H), 5.98 (s, 1H), 6.96 (d,J=8 Hz, 1H), 7.04 (d, J=8, Hz, 1H), 7.17 (S, 1H). LC-MS calcd forC₂₅H₂₉ClN₂O₅: 472.18, found (M+H⁺): 473.1 m/z.

Step 1: 2-(Chloromethyl)-6-methylpyrimidin-4(3H)-one

Prepared according to a reported procedure: Okabe, T.; Hirano, M.;Mukai, K. U.S. Pat. No. 4,326,058 (Apr. 20, 1982). Yield: 12%.

¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (s, 3H), 4.42 (s, 2H), 6.16 (s, 1H),12.61 (br s, 1H). LC-MS (APCI) calcd for C₆H₇ClN₂O: 158.02; found(M+H⁺): 159.0 m/z.

Example B(55)2-({6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)quinazolin-4(3H)-one

The title compound was prepared as described in Example B(53), employing2-(bromomethyl)quinazolin-4(3H)-one in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole. Yield: 16%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.70 (m, 8H), 2.20-2.25 (m, 2H), 2.35(m, 1H), 2.45-2.60 (m, 3H, overlap with DMSO-d₅), 2.73 (d, J=18 Hz, 1H),3.52 (m, 2H, overlap with H₂O peak), 3.76 (s, 3H), 6.92 (d, J=8 Hz, 1H),6.96 (d, J=8 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 7.21 (s, 1H), 7.36 (t, J=8Hz, 1H), 7.50 (t, J=8 Hz, 1H), 7.97 (d, J=8 Hz, 1H). LC-MS calcd forC₂₈H₂₉ClN₂O₅: 508.18, found (M+H⁺): 509.1 m/z.

Step 1. 2-(Bromomethyl)quinazolin-4(3H)-one

The title compound was made by a slight modification of a reportedprocedure (Bergman, J.; Brynolf, A. Tetrahedron 1990, 46, 1295). A3-necked 500-mL round bottomed flask was charged with2-(methyl)quinazolin-4(3H)-one (50.09 g, 0.303 mol), 200 mL of dry DMF,and N-bromosuccinimide (54.53 g, 0.303 mol, 1 equiv). The reactionmixture was warmed to 40° C. and maintained at this temperature for 2 h.The mixture was cooled to room temperature and allowed to stand for 4 d.The resulting tan slurry was filtered, and the filter cake washed withether (3×50 mL), and dried in vacuo. The crude solid was suspended inmixture of 95% ethanol (600 mL) and water (6 mL) and the mixture heatedto boiling. The hot slurry was cooled to room temperature, chilled in anice bath, and filtered. The cake was washed with chilled 95% ethanol (50mL), followed by ether (2×50 mL), then dried in vacuo, affording 52.90 gof material containing 11% starting material. This was recrystallizedfrom hot (95° C.) DMF (750 mL). Upon cooling to room temperature, theslurry was filtered, and the cake washed with DMF (80 mL), and methanol(3×50 mL), then dried in vacuo at 50° C., affording 39.40 g (54%). Theproduct was found to be 98% pure by both HPLC and ¹H NMR.

¹H NMR (300 MHz, DMSO-d₆) δ 4.40 (s, 2H), 7.55 (t, J=8 Hz, 1H), 7.67 (d,J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 12.57 (br s,1H). LC-MS (APCI) calcd for C₉H₇BrN₂O: 238.0; found (M+H⁺) 239.1, 241.1(1:1) m/z.

Example B(56)2-([6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl)thieno[3,2-d]pyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one (Step 1) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole. Yield: 22%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.5-1.7 (m, 8H), 1.90-2.18 (m, 2H), 2.35 (m,1H), 2.52 (m, 3H,), 2.70 (d, J=18 Hz, 1H), 3.53 (ABQ, J=15 Hz, 2H), 3.72(s, 3H, overlap with H₂O peak), 6.72 (d, J=5.1 Hz, 1H), 6.96 (d, J=8.6Hz, 1H), 7.04 (dd, J=8.6, 2.1 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.97 (t,J=5.1 Hz, 1 H). LC-MS (APCI) calcd for C₂₆H₂₇ClN₂O₅S: 514.13; found(M+H⁺) 515.0 m/z.

Step 1: 2-(Chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one

This compound was prepared by a modification of a method reported forrelated fused pyrimidine-4(3H)-ones: (1) Shishoo, C. J.; Devani, M. B.;Pathak, U.S.; Ananthan, S.; Bhadti, V. S.; Ullas, G. V.; Jain, K. S.;Rathod, I. S.; Talati, D. S.; Doshi, N. H. J. Heterocyclic Chem. 1984,21, 375, and (2) Gerecke, M.; Kyburz, E.; Borer, R.; Gassner, W.Heterocycles 1994, 39, 693). An oven-dried 1-L round bottomed flask wascharged with chloroacetonitrile (21.86 g, 0.29 mol, 1.3 equiv), methyl3-aminothiophene-2-carboxylate (35 g, 0.223 mol), and 4 M HCl in1,4-dioxane (350 mL). The reaction mixture was stirred at roomtemperature for 1 d. The mixture was evaporated to dryness. The residuewas dissolved in water (600 mL) and treated with aqueous 10% sodiumbicarbonate to a pH of 8. The resulting slurry was filtered, and thecake washed with water and dried, affording 38.2 g (85%) of the titleproduct.

¹H NMR (DMSO-d₆) δ 4.58 (s, 2H), 7.42 (d, J=5.3 Hz, 1H), 8.22 (d, J=5.3Hz, 1H), 12.84 (br s, 1H). LC-MS (APCI) calcd for C₇H₅ClN₂OS: 200.0;Found (M+H⁺): 201.0 m/z.

Example B(57)2-({6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-6,7-dimethoxyquinazolin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one (Step 1) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole. Yield: 18%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55-1.67 (m, 8H), 1.85-2.1 (m, 2H), 2.36(m, 1H), 2.5-2.6 (m, 3H), 2.71 (d, J=18 Hz, 1H), 3.59 (s, m overlap,5H), 3.73 (s, 3H, overlap with H₂O peak), 3.79 (s, 3H, overlap with H₂Opeak), 6.64 (s, 1H), 6.90 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 1.6 Hz,1H), 7.20 (d, J=1.6 Hz, 1H), 7.34 (s, 1H). LC-MS (APCI) calcd forC₃₀H₃₃ClN₂O₇: 568.20; found (M+H⁺) 569.1 m/z.

Step 1: 2-(Chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one

The title compound was prepared as described in Step 1 of Example B(56),except using methyl 2-amino-4,5-dimethoxy benzoate in place of methyl3-aminothiophene-2-carboxylate. The crude product (20 g) obtained from22.8 g (0.108 mol) of 2-amino-4,5-dimethoxy benzoate was recrystallizedfrom a hot (70° C.) mixture of ethyl acetate (600 mL) and methanol (200mL), to give 13.3 g (50%) of the title product.

¹H NMR (DMSO-d₆) δ 3.87 (s, 3H), 3.90 (s, 3H), 4.52 (s, 2H), 7.15 (s,1H), 7.43 (s, 1H), 12.4 (v br s, 1H). LC-MS (APCI, Neg) calcd forC₁₁H₁₁ClN₂O₃: 254.05; found (M−H⁺) 253.0 m/z.

Example B(58)7-[(6-{2-[3-Chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl]-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The title compound was prepared as described in Example B(53), using7-(chloromethyl)-3-methyl-5H-(1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared according to a reported procedure: Doria, G.; Passarotti, C.;Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari,G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(from Step 4, below) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 1%.

¹H NMR (300 MHz, DMSO-d₆)□ 0.31 (m, 2H), 0.56 (m, 2H), 1.22 (m, 1H),1.23-1.65 (m, 8H), 1.92 (m, 2H), 2.33 (m, 1H), 2.48-2.75 (s, m, 7H,overlap with DMSO-d₅), 3.45 (m, 2H, overlap with H₂O peak), 3.84 (d,J=7.8 Hz, 2H), 4.87 (s, 2H), 5.20 (s, 1H), 6.16 (s, 1H), 6.93 (d, J=9Hz, 1H), 7.01 (dd, J=9, 1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H). LC-MS(APCI) calcd for C₃₀H₃₃ClN₂O₅S: 568.18; found (M+H⁺) 569.0 m/z.

Step 1. 3-[4-(Benzyloxy)-3-chlorophenyl]-1-cyclopentylpropan-1-one

A solution of 3-[4-(benzyloxy)-3-chlorophenyl]propanoic acid (80 g, 0.28mol, obtained as described: Kuchar, M.; Brunova, B.; Rejholec, V.;Roubal, Z.; Nemecek, O. Collect. Czech. Chem. Commun 1981, 46, 1173) inDCE (500 mL) was treated with oxalyl chloride (26.5 mL, 0.30 mol, 1.05equiv). After stirring for 2 min, DMF (0.2 mL) was added, and stirringcontinued for an additional 3 h. The volatiles were removed in vacuo,affording a quantitative yield of the acid chloride, a green oil, whichwas used directly in the next step. The crude acid chloride thusobtained was dissolved in CH₂Cl₂ (1 L), and added dropwise via anaddition funnel to 2-mercaptopyridine (30.5 g, 0.28 mol, 1 equiv) inCH₂Cl₂ (3 L). The reaction mixture was stirred for an additional 3 h at23° C. The mixture was treated with 1.0 N NaOH (320 mL), and extractedwith ethyl acetate (3×200 mL). The combined extracts were washed withaqueous NaHCO₃ and brine, dried over MgSO₄, filtered, and evaporated.The resulting crude S-pyridin-2-yl3-[4-(benzyloxy)-3-chlorophenyl]propanethioate, an amber oil, was useddirectly in the next step. This thioester intermediate was dissolved inTHF (450 mL), the solution chilled in a dry ice bath to −70° C., andtreated dropwise at this temperature with a 2M solution ofcyclopentylmagnesium bromide in diethyl ether (145 mL, 0.28 mol, 1equiv). When the addition was complete, a sample taken from theresulting peach-colored slurry was treated with 5% HCl, and subjected toTLC analysis on silica gel using 20% ethyl acetate in hexanes. AUV-active spot at Rf=0.5 stained orange with 2,4-DNP. The reactionmixture was warmed to room temperature, then treated with 5% aqueous HCl(350 mL) and diethyl ether (20 mL). The layers were separated and theorganic phase washed with aqueous NaHCO₃ and brine, dried over MgSO₄,filtered, and evaporated, affording an amber oil (93 g). This waschromatographed on silica gel using 10% ethyl acetate in hexanes,affording 48 g (51% overall) of the cyclopentyl ketone as a pale yellowoil.

¹H NMR (DMSO-d₆) d 1.45-1.8 (m, 8H), 2.7-2.9 (m, 5H), 5.15 (s, 2H), 7.10(s, 2H), 7.3-7.5 (m, 6H). LC-MS (neg) calcd for C₂₁H₂₃ClO₂, 342.14;found [M-1]: 341.1.

Step 2. 3-(3-Chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one

A mixture of 3-[4-(benzyloxy)-3-chlorophenyl]-1-cyclopentylpropan-1-one(48 g, 0.140 mole), from Step 1, and 10% palladium-on-carbon (11.52 g of50 wt % wet, 0.005 mol, 3.5 mole %) in ethyl acetate (500 mL) wasdegassed and purged with hydrogen three times. The reaction was stirredwith 1 atm H₂ for 4 h, resulting in complete conversion. The mixture wasfiltered through a fine fritted glass funnel and the filtrateconcentrated in vacuo, affording a yellow oil which crystallized oncooling. This material was recrystallized from two parts of isopropylether, affording 22 g (62%) of the title product. mp 88-90° C.

¹H NMR (DMSO-d₆) δ 1.4-1.75 (m, 8H), 2.5-2.7 (m, 4H), 2.9 (m, 1H), 6.83(d, J=8.3 Hz, 1H), 6.94 (dd, J=8.3, 1.9 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H),9.86 (br s, 1H). MS calcd for C₁₄H₁₇ClO₂, 252.09, found [M+1)]: 253.10.

Step 3:3-[3-Chloro-4-(cyclopropylmethoxy)phenyl]-1-cyclopentylpropan-1-one

A solution of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one((25 g, 0.099 mol, from Step 2) in 1:1 DMF/CH₃CN (200 mL) was treatedwith K₂CO₃ (15 g, 0.109 mol, 1.1 equiv), and the mixture stirred for 15min. A solution of (bromomethyl)cyclopropane (17.4 g, 0.129 mol, 1.3equiv) in DMF (50 mL) was added dropwise, and the reaction mixtureheated to 100° C. for 1 h. The volatiles were removed in vacuo. Theresidue was dissolved in a minimal amount of ethyl acetate, and thissolution washed with water, dried over Na₂SO₄, filtered, and evaporated.Chromatographic purification of the residue on silica gel usinghexanes/ethyl acetate afforded 29.12 g (96%) of the title compound.

¹H NMR (CDCl₃) δ 0.32 (m, 2H), 0.58 (m, 2H), 1.23 (m, 1H), 1.64 (m, 8H),2.70 (m, 5H), 3.8 (d, J=6 Hz, 2H), 6.78 (d, J=9 Hz, 1H), 6.93 (d, J=9Hz, 1H), 7.13 (s, 1H). MS calcd for C₁₈H₂₃ClO₂, 306.83, found [M+1)]:307.0.

Step 4.6-{-[3-Chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

An oven-dried, 500-mL 3-necked round-bottomed flask, cooled under ablanket of N₂, was charged with NaH (1.48 g, 61.74 mmol) and 25 mL dryTHF. The slurry was cooled to −40° C. in a dry ice/CH₃CN bath andtreated slowly with a cold solution of methyl acetoacetate (6.83 g, 58.8mmol) in THF (30 mL), delivered via syringe at such a rate that theinternal temperature stays within a 5° C. interval. The mixture wasstirred for 30 min, then cooled to −70° C. with a dry ice/acetone bath.The mixture was treated with n-BuLi (23.5 mL, 61.74 mmol) at −70° C.,and stirred at this temperature for an additional 45 min. To theresulting solution of acetoacetate dianion was added a solution of3-[3-chloro-4-(cyclopropylmethoxy)phenyl]-1-cyclopentylpropan-1-one(15.03 g, 49 mmol, from Step 3) in THF (50 mL) via an addition funnel,at such a rate that a reaction temperature of −70° C. is maintained.After stirring at this temperature for an additional 1 h, the reactionmixture was allowed to warm to room temperature over 3 h, then quenchedwith 4 M NH₄Cl (aq) (30.87 mL). After stirring at room temperature for10 min, the mixture is concentrated in vacuo. To the oily residue wasadded water, then the mixture extracted with ethyl acetate (3×100 mL).The ethyl acetate solution was dried over Na₂SO₄, filtered, andconcentrated to a viscous resin, which was chromatographed on silica gelwith 5:1 hexanes/ethyl acetate, affording 14.82 g (71%) of the hydroxyester intermediate. This intermediate was dissolved in THF (100 mL)added to 1 M NaOH (aq) (3 L), and the resulting mixture stirred at roomtemperature for 3 h. The mixture was acidified with 1 M aqueous HCl (1.5L) to a pH 2. The product was extracted into dichloromethane (3×400 mL),and the extract dried over Na₂SO₄, filtered, and concentrated to aresin. The resin was chromatographed on silica gel using 3:1hexanes/ethyl acetate, and the resulting foam crystallized from ethylacetate/hexanes to obtain 4.45 g, (23% overall) of the product as anoff-white solid.

¹H NMR (300 MHz, CDCl₃) d 0.38 (d, J=5 Hz, 2H), 0.65 (d, J=7.5 Hz, 2H),1.32 (m, 1H), 1.40-1.85 (m, 8H), 1.95 (m, 2H), 2.27 (m, 1H), 2.61 (t,J=8.2 Hz, 2H), 2.77 (s, 2H), 3.43 (s, 2H), 3.86 (d, J=6.7 Hz, 2H), 6.84(d, 1H, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 7.16 (s, 1H). MS calcdfor C₂₂H₂₇ClO₄: 390.90, MS found, [M+1]: 391.

Example B(59)7-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The title compound was prepared as described in Example B(53), using7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared according to a reported procedure: Doria, G.; Passarotti, C.;Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari,G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 18%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.73 (m, 8H), 1.78-2.0 (m, 2H), 2.35(m, 1H), 2.48-2.58 (m, 2H, overlap with DMSO-d₅), 2.64 (s, m, overlap,4H), 2.78 (d, J=18 Hz, 1H), 3.44 (s, 2H), 3.78 (s, 3H, overlap with H₂Opeak), 3.85 (s, 3H), 5.80 (s, 1H), 6.70 (s, 1H), 6.97 (s, 1H), 7.11 (s,1H), 10.96 (br s, 1H). LC-MS (APCI) calcd for C₂₈H₃₁ClN₂O₆S: 558.16;found (M+H⁺) 559.0 m/z.

Example B(60) Methyl5-({6-cyclopentyl-4-hydroxy-6-[2-(4-methoxyphenyl)ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl)isoxazol-3-ylcarbamate

The title compound was prepared as described in Example B(53), usingmethyl 5-(bromomethyl)isoxazol-3-ylcarbamate (prepared as described:Sircar, J. C.; Capiris, T. U.S. Pat. No. 4,489,077, Dec. 18, 1984) inplace of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentydihydro-2H-pyran-2,4(3H)-dione.Yield: 13%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.15-1.65 (m, 8H), 1.80 (m, 2H), 2.25 (m,1H), 2.39-2.51 (m, 3H, overlap with DMSO-d₅), 2.68 (d, J=17.4 Hz, 1H),3.51 (s, 2H), 3.56 (s, 3H), 3.61 (s, 3H), 6.24 (s, 1H), 6.72 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 10.47 (s, 1H), 11.15 (br s, 1H). LC-MS(APCI) calcd for C₂₅H₃₀N₂O₇: 470.21; found (M+H⁺) 471.1 m/z.

Example B(61)7-({6-Cyclopentyl-4-hydroxy-6-[2-(4-methoxyphenyl)ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The title compound was prepared as described in Example B(53), using7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared according to a reported procedure: Doria, G.; Passarotti, C.;Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari,G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 17%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.2-1.65 (m, 8H), 1.87 (m, 2H), 2.31 (m,1H), 2.48-2.53 (d, m, 3H, overlap with DMSO-d₅), 2.59 (s, 3H), 2.71 (d,J=17.1 Hz, 1H), 3.38 (ABQ pattern, J=15.8 Hz, 2H), 3.64 (s, 3H), 5.77(s, 1H), 6.73 (d, J=8.7 Hz, 2H), 6.91 (s, 1H), 6.98 (d, J=8.7 Hz, 2H),10.9 (br s, 1H). LC-MS (APCI) calcd for C₂₇H₃₀N₂O₅S: 494.19; found(M+H⁺) 495.0 m/z.

Example B(62)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-3-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (Step 1, below) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 7%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.10 (t, J=7.8 Hz, 3H), 1.25-1.73 (m, 8H),1.89 (m, 2H), 2.33 (m, 1H), 2.43-2.53 (m, 2H, overlap with DMSO-d₅),2.58 (q, m, overlap, 3H), 2.76 (d, J=18 Hz, 1H), 3.75 (ABQ pattern, J=16Hz, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 6.71 (s, 11), 7.10 (s, 1H), 11.31(br s, 1H). LC-MS (APCI) calcd for C₂₅H₃₁ClN₂O₆: 490.19; found (M+H⁺)491.0 m/z.

Step 1: 5-(Chloromethyl)-3-ethyl-1,2,4-oxadiazole

To crude N-hydroxypropanimidamide (80 g, 0.91 mol), obtained frompropionitrile and hydroxylamine (Moloney, G. P.; Martin, G. R.; Mathews,N.; Maclennan, S.; Dodsworth, S.; Sang, P. Y.; Knight, C.; Maxwell, M.;Glen, R. C. J. Chem. Soc Perkin I 1999, 19, 2725), was addedchloroacetyl chloride (411 g, 3.64 mol, 4 equiv). After the initialexothermic reaction subsided, the mixture was refluxed for 70 min. Thereaction mixture was cooled to room temperature, and the excesschloroacetyl chloride evaporated. The residue was dissolved in ethylacetate, diluted with hexanes, and filtered to remove dark solidimpurities. The filtrate was evaporated, treated with ice-cold aqueousNaHCO₃, and extracted with ethyl acetate (2×150 mL). The extract wasdried over Na₂SO₄, filtered, and the solvent evaporated, affording 76.25g of an oil. This was subjected to fractional distillation, affording16.5 g (14%) of the title product (bp 36° C./0.05 Torr; lit bp 88° C./35Torr: Hagerty, J. D. U.S. Pat. No. 3,956,498, May 11, 1976).

¹H NMR (CDCl₃) d 1.31 (t, J=7 Hz, 3H), 2.75 (q, J=7 Hz, 2H), 4.64 (s,2H). LC-MS (APCI) calcd for C₅H₇ClN₂O: 146.02; found (M+H⁺): 147.0 m/z.

Example B(63)2-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-6,7-dimethoxyquinazolin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example B(57),Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, andusing6-(2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 20%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.75 (m, 8H), 1.85 (m, 1H), 2.05 (m,1H), 2.37 (m, 1H), 2.50 (m, 2H, overlap with DMSO-d₅), 2.53 (d, J=18 Hz,1H), 2.69 (d, J=18 Hz, 1H), 3.59 (m, 2H, overlap with H₂O), 3.62 (s, 3H,overlap with H₂O), 3.67 (s, 3H, overlap with H₂O), 3.81 (s, 3H, overlapwith H₂O), 3.84 (s, 3H, overlap with H₂O), 6.61 (s, 1H), 6.63 (s, 1H),7.13 (s, 1H), 7.39 (s, 1H). LC-MS (APCI) calcd for C₃₁H₃₅ClN₂O₈: 598.21;found (M+H⁺) 599.1 m/z.

Example B(64)2-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)thieno[3,2-d]pyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one (Example B(56),Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, andusing6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 20%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.67 (m, 8H), 1.90 (m, 1H), 2.04 (m,1H), 2.32 (m, 1H), 2.40-2.54 (m, 3H, overlap with DMSO-d₅), 2.71 (d,J=18 Hz, 1H), 3.52 (ABQ pattern, J=15 Hz, 2H, overlap with H₂O), 3.69(s, 3H), 3.80 (s, 3H), 6.65 (s, 1H), 6.71 (d, J=5.4 Hz, 1H), 7.05 (s,1H), 7.96 (d, J=5.4 Hz, 1H), 10.88 (br s, 1H), 12.26 (br s, 1H). LC-MS(APCI) calcd for C₂₇H₂₉ClN₂O₆S: 544.14; found (M+H⁺) 544.9 m/z.

Example B(65)2-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)quinazolin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(bromomethyl)-quinazolin-4(3H)-one (Example B(55), Step 1) in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 19%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.33-1.74 (m, 8H), 1.99 (m, 1H), 2.23 (m,1H), 2.37 (m, 1H), 2.45-2.53 (m, 2H, overlap with DMSO-d₅), 2.58 (d,J=17.5 Hz, 1H), 2.78 (d, J=17.5 Hz, 1H), 3.59 (ABQ pattern, J=16.6 Hz,2H), 3.73 (s, 3H), 3.84 (s, 3H), 6.69 (s, 1H), 7.01 (d, J=8 Hz, 1H),7.13 (s, 1H), 7.42 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 8.03 (d, J=8Hz, 1H). LC-MS (APCI) calcd for C₂₉H₃₁ClN₂O₆: 538.19; found (M+H⁺) 539.0m/z.

Example B(66)6-([6-Cyclopentyl-4-hydroxy-6-[2-(4-methoxyphenyl)ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-2-pyridin-2-ylpyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53), using6-(chloromethyl)-2-pyridin-2-ylpyrimidin-4(3H)-one in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 11%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32-1.67 (m, 8H), 1.92 (m, 2H), 2.38 (m,1H), 2.45-2.52 (m, 2H, overlap with DMSO-d₅), 2.60 (d, J=17.7 Hz, 1H),2.80 (d, J=17.7 Hz, 1H), 3.52 (m, 2H, overlap with H₂O), 3.66 (s, 3H,overlap with H₂O), 6.07 (s, 3H), 6.68 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 7.60 (dd, J=7.5, 4.8 Hz, 1H), 7.93 (td, J=8 Hz, 1.5 Hz, 1H),8.18 (d, J=8 Hz, 1H), 8.70 (d, J=4.8 Hz, 1H), 10.98 (br s, 1H). LC-MS(APCI) calcd for C₂₉H₃₁N₃O₅: 501.23; found (M+H⁺) 502.1 m/z.

Example B(67)6-[(6-{2-[4-(Benzyloxy)phenyl]ethyl}-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl]-2-cyclopropylpyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53), using6-(chloromethyl)-2-cyclopropylpyrimidin-4(3H)-one in place of5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-2-[4-(benzyloxy)phenyl]ethyl}-cyclopentyldihydro-2H-pyran-2,4-(3H)-dione(Step 6, below) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 12%.

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (m, 4H), 1.15-1.65 (m, 8H), 1.82-1.92(m, 3H), 2.34 (m, 1H), 2.38-2.58 (m, 3H, overlap with DMSO-d₅), 2.75 (d,J=18 Hz, 1H), 3.29 (ABQ pattern, J=16.7 Hz, 2H), 5.05 (s, 2H), 5.72 (s,1H), 6.90 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.43-7.28 (m, 5H).LC-MS (APCI) calcd for C₃₃H₃₆N₂O₅: 540.26; found (M+H⁺) 541.1 m/z.

Step 1: 3-(4-Hydroxyphenyl)propionic Acid Methyl Ester

A solution of HCl in dioxane (4.0 M, 7.4 mL) was added to a solution of4-hydroxyphenylpropionic acid (15.0 g, 90.3 mmol) in MeOH (500 mL). Thereaction mixture was stirred overnight and then evaporated. The residuewas evaporated from benzene (2×50 mL) to provide the product as an oil,which was used without further purification.

Step 2: 3-(4-Benzyloxyphenyl)propionic Acid Methyl Ester

Benzyl bromide (12.9 mL, 108 mmol), K₂CO₃ (15.0 g, 109 mmol) and the3-(4-hydroxyphenyl)propionic acid methyl ester from Step 1 above werecombined in acetone (300 mL) and refluxed 40 h. The crude reactionmixture was filtered and the cake washed with acetone (2×100 mL). Thefiltrate was evaporated and the residue was triturated with MeOH (50 mL,6 mL, 4 mL) to provide the product as a solid which was used withoutfurther purification.

Step 3: 3-(4-Benzyloxyphenyl)propionic Acid

An aqueous solution of NaOH (1 M, 270 mL) was added to a mixture of the3-(4-benzyloxyphenyl)propionic acid methyl ester from Step 2 above inMeOH (600 mL) and the reaction was stirred overnight. The crystallineppt was collected by filtration, air dried and then partitioned betweenEtOAc/Et₂O/1 M HCl (500 mL, 250 mL, 150 mL). The organic phases weredried over MgSO₄ and evaporated to give the product as a white solid(16.2 g, 70%, 3 Steps).

¹H NMR (CDCl₃) δ 2.61-2.68 (m, 2H), 2.86-2.93 (m, 2H), 5.03 (s, 2H),6.88-6.93 (m, 2H), 7.10-7.15 (m, 2H), 7.28-7.45 (m, 5H).

Step 4: 3-(4-Benzyloxyphenyl)thiopropionic Acid S-pyridin-2-yl Ester

3-(4-Benzyloxyphenyl)propionic acid (5.40 g, 21.1 mmol) from Step 3above, triphenylphosphine (7.18 g, 27.4 mmol) and 2,2′-dipyridyldisulfide (5.80 g, 26.3 mmol) were combined successively in CH₂Cl₂ (24mL). The reaction mixture was stirred 1 h and then loaded directly ontoa column for purification by flash chromatography (33% EtOAc in hexanes)to give a residue. This residue was washed with hexanes (20 mL) and thesolid, partially crystalline material was collected by filtration andair dried to give the product (7.11 g, 97%).

¹H NMR(CDCl₃) δ 2.98 (s, 4H), 5.04 (s, 2H), 6.88-6.94 (m, 2H), 7.10-7.16(m, 2H), 7.25-7.45 (m, 6H), 7.57-7.60 (m, 1H), 7.70-7.77 (m, 1H),8.60-8.64 (m, 1H).

Step 5: 3-(4-Benzyloxyphenyl)-1-cyclopentylpropan-1-one

3-(4-Benzyloxyphenyl)thiopropionic acid S-pyridin-2-yl ester (3.00 g,8.58 mmol) from Step 4 above was dissolved in dry THF (45 mL) and cooledto −78° C. A solution of cyclopentylmagnesium bromide in Et₂O (2.0 M,4.51 mL, 9.02 mmol) was added dropwise along the sides of the reactionvessel. After stirring 35 min, the cooling bath was removed. Thereaction mixture was quenched with saturated aq. NH₄Cl upon reachingambient temperature and extracted with Et₂O (500 mL). The organic phasewas washed with brine (50 mL), dried over MgSO₄ and evaporated. Theresidue was purified by flash column chromatography (10% EtOAc inhexanes) to give the product (2.22 g, 84%) as a white semi-crystallinematerial.

¹H NMR (CDCl₃) δ 1.48-1.83 (m, 8H), 2.69-2.77 (m, 2H), 2.79-2.88 (m,3H), 5.03 (s, 2H), 6.86-6.92 (m, 2H), 7.07-7.12 (m, 2H), 7.28-7.45 (m,5H).

Step 6:6-[2-(4-Benzyloxyphenyl)ethyl]-6-cyclopentyldihydropyran-2,4-dione

Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL)and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) werecarefully added and the reaction mixture was stirred for 20 min. Asolution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was addeddropwise and the resulting mixture was stirred an additional 20 min. Asolution of 3-(4-benzyloxyphenyl)-1-cyclopentylpropan-1-one (2.33 g,7.55 mmol) from Step 5 above in THF (37 mL) was added dropwise. Afterstirring 1 h, the reaction mixture was quenched with saturated aq NH₄Cl(100 mL) and extracted with Et₂O (600 mL). The organic phase was driedover MgSO₄ and evaporated. The residue was then stirred overnight in amixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of anaq solution of 10% aq KHSO₄ (50 mL) the resulting mixture was stirred 30min and then extracted with Et₂O (600 mL). The organic phase was washedwith brine, dried over MgSO₄ and evaporated. The residue was purified byflash column chromatography (50% EtOAc in hexanes) to give the product(1.54 g, 52%) as a white foam.

¹H NMR (CDCl₃) δ 1.39-2.04 (m, 10H), 2.21-2.33 (m, 1H), 2.56-2.67 (m,2H), 2.76 (s, 2H), 3.41 (s, 2H), 5.03 (s, 2H), 6.87-6.93 (m, 2H),7.02-7.08 (m, 2H), 7.28-7.44 (m, 5H).

Example B(68)2-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-6-methylpyrimidin-4(3H)-one

The title compound was prepared as described in Example B(53), using2-(chloromethyl)-6-methylpyrimidin-4(3H)-one (Example B(54), Step 1) inplace of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 19%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.75 (m, 8H), 1.87 (s, m overlap, 4H),2.05 (m, 1H), 2.36 (m, 1H), 2.43-2.50 (m, 2H, overlap with DMSO-d₅),2.56 (d, J=17.5 Hz, 1H), 2.67 (d, J=17.5 Hz, 1H), 3.48 (m, 2H, overlapwith H₂O), 3.77 (s, 3H), 3.84 (s, 3H), 5.98 (s, 1H), 6.71 (s, 1H), 7.09(s, 1H). LC-MS (APCI) calcd for C₂₆H₃₁ClN₂O₆: 502.19; found (M+H⁺) 503.0m/z.

Example B(69)6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-3-[(1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using6-cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione(Step 3, below) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 12%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.68 (m, 8H), 2.04 (m, 2H), 2.13 (s,3H), 2.34 (m, 1H), 2.40-2.63 (m, 3H, overlap with DMSO-d₅), 2.71 (d,J=17.4 Hz, 1H), 3.48 (m, 2H, overlap with H₂O), 3.76 (s, 3H), 7.15 (t,J=55 Hz, 1H), 7.18 (m, 2H), 7.52 (t, J=7.8 Hz, 1H). LC-MS (APCI) calcdfor C₂₄H₂₈F₃N₃O₃: 463.21; found (M+H⁺): 464.1 m/z.

Step 1. 4-Bromo-1-(difluoromethyl)-2-fluorobenzene

A solution of 2-fluoro-4-bromobenzaldehyde (50 g, 0.245 mol) in CH₂Cl₂(500 mL) was treated with a solution of DAST (44 g, 0.271 mol, 1.1equiv) in CH₂Cl₂ (200 mL) dropwise at such a rate that the internaltemperature was maintained below 35° C. The reaction temperature wasalso controlled using an ice/water bath. Once the addition wascompleted, the reaction was stirred at room temperature for 14 h. Thereaction mixture was poured over crushed ice and neutralized withNaHCO₃. The organic layer was separated, the aqueous layer extractedwith CH₂Cl₂, and the combined extracts dried over Na₂SO₄ andconcentrated. The residue was purified by fractional distillation togive 44 g (80%) of desired product (bp 43° C./1 Torr).

¹H NMR (DMSO-d₆) d 7.10 (t, 1H, J=54 Hz), 7.46 (m, 3H). MS(APCI) calcdfor C₇H₄F₃Br, 225.06; found [M-19(—F)]: 206 m/z.

Step 2. 1-Cyclopentyl-3-[4-(difluoromethyl)-3-fluorophenyl]propan-1-one

A mixture of 1-cyclopentyl-2-propen-1-ol (34 g, 0.266 mol),2-fluoro-4-bromo-difluoromethyl benzene, (40 g, 0.177 mol, 1.5 equiv),and NaHCO₃ (17.8 g, 0.212 mol, 1.2 equiv) in anhydrous NMP (200 mL) washeated to 140° C. for 1 h, resulting in complete conversion by TLC. Thereaction mixture was poured into water and extracted with CH₂Cl₂. Theorganic layer was separated, washed with brine and dried over anhydrousNa₂SO₄. After the removal of the solvent, the residue was purified bycolumn chromatography using hexanes/ethyl acetate, and theproduct-containing fractions combined and concentrated. The residue wasfractionally distilled through a Vigreux column to give 16 g (33%) ofthe desired product (bp 100° C./0.2 Torr).

¹H NMR (CDCl₃) d 1.57 (m, 8H), 2.81 (m, 4H), 3.09 (m, 1H), 6.86 (t, 1H,J=57 Hz), 6.95 (m, 2H), 7.51 (t, 1H, J=7.5 Hz). MS (APCI) calcd forC₁₆H₁₇F₃O, 270.29; found [M-19(—F)]: 251.02 m/z.

Step 3.6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared as described in Step 4 of Example B(58),using 1-cyclopentyl-3-[4-(difluoromethyl)-3-fluorophenyl]propan-1-one(Step 2, above) in place of3-[3-chloro-4-(cyclopropylmethoxy)phenyl]-1-cyclopentylpropan-1-one,with the exception that the intermediate hydroxyester was not purified.The crude product, a viscous yellow oil, was dissolved in a minimalamount of ethyl ether, diluted with hexanes and cooled, affording 4 g(16%) of the product as a white solid.

¹H NMR (CDCl₃) d 1.66 (m, 8H), 1.94 (t, 2H), 2.26 (m, 1H), 2.75 (m, 4H),3.42 (s, 2H), 6.67-7.04 (m, 3H,), 7.5 (t, 1H, J=7.5). MS calcd forC₁₉H₂₁F₃O₃: 354.363; found [M-19(—F)]: 335.2 m/z.

Example B(70)6-{2-[3-Chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyl-3-[(1.3-dimethyl-1H-1,2,4-triazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using6{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(Example B(58), Step 4) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 9%.

¹H NMR (300 MHz, DMSO-d₆) δ 0.26 (m, 2H), 0.50 (m, 2H), 1.13-1.65 (m,9H), 1.92 (m, 2H), 2.08 (s, 3H), 2.29 (m, 1H), 2.35-2.50 (m, 3H, overlapwith DMSO-d₅), 2.69 (d, J=17.7 Hz, 1H), 3.57 (ABQ pattern, J=15.6 Hz,2H, overlap with H₂O peak), 3.69 (s, 3H, overlap with H₂O peak), 3.80(d, J=6.9 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4 Hz, 1.9 Hz,1H), 7.16 (d, J=1.9 Hz, 1H). LC-MS (APCI) calcd for C₂₇H₃₄ClN₃O₄:499.22; found (M+H⁺): 500.1 m/z.

Example B(71)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-3-[(1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 14%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.2-1.7 (m, 8H), 1.87 (m, 2H), 2.19 (s, 3H),2.32 (m, 1H), 2.35-2.52 (m, 2H, overlap with DMSO-d₅), 2.56 (d, J=17.7Hz, 1H), 2.76 (d, J=17.7 Hz, 1H), 3.68 (s, 2H), 3.78 (s, 6H), 3.85 (s,3H), 6.71 (s, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C₂₅H₃₂ClN₃O₅:489.20; found (M+H⁺): 490.1 m/z.

Example B(72) Methyl5-[(6-cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl]isoxazol-3-ylcarbamate

The title compound was prepared as described in Example B(53), usingmethyl 5-(bromomethyl)isoxazol-3-ylcarbamate (prepared as described:Sircar, J. C.; Capiris, T. U.S. Pat. No. 4,489,077, Dec. 18, 1984) inplace of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione(ExampleB(69), Step 3) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 6%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.75 (m, 8H), 1.94 (m, 2H), 2.35 (m,1H), 2.40-2.70 (m, 3H, overlap with DMSO-d₅), 2.76 (d, J=18.3 Hz, 1H),3.59 (m, 2H, overlap with H₂O), 3.63 (s, 3H), 6.31 (s, 1H), 7.08 (t,J=55 Hz, overlap with m, combined: 3H), 7.50 (t, J=7.5 Hz, 1H), 10.55(s, 1H), 11.26 (s, 1H). LC-MS (APCI) calcd for C₂₅H₂₇F₃N₂O₆: 508.18;found (M+H⁺): 509.1 m/z.

Example B(73)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)methyl]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]pyridine (from Step 1, below)in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 9%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.75 (m, 8H), 1.76-2.03 (m, 2H), 2.34(m, 1H), 2.4-2.55 (m, 2H, overlap with DMSO-d₅), 2.62 (d, J=17.7 Hz,1H), 2.81 (d, J=17.7 Hz, 1H), 3.74 (s, 3H, overlap with H₂O), 3.80 (s,3H), 3.90 (ABQ pattern, J=16.8 Hz, 2H), 6.66 (s, 1H), 7.13 (s, 1H), 7.55(m, 1H), 7.81 (m, 2H), 8.70 (d, J=4.8 Hz, 1H), 11.43 (br s, 1H). LC-MS(APCI) calcd for C₂₈H₃₀ClN₃O₆: 539.18; found (M+H⁺): 540.1 m/z.

Step 1: 2-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]pyridine

The title compound was prepared by a modification of a reported method:a) Mylari, B. L.; Beyer, T. A.; Scott, P. J.; Aldinger, C. E.; Dee, M.F.; Siegel, T. W.; Zembrowski, W. J. J. Med. Chem. 1992, 35, 457, and b)Palazzo, G.; Tavella, M.; Strani, G.; Silvestrini, B.; J. Med. Pharm.Chem. 1961, 4, 351. To a suspension ofN′-hydroxypyridine-2-carboximidamide (25.0 g, 0.182 mol) in chloroform(350 mL) was added chloroacetyl chloride (20.5 g, 0.182 mol, 1 equiv)and triethylamine (20.23 g, 0.2 mol, 1.1 equiv). When most of thetriethylamine had been added, the suspension turned to a clearlight-yellow solution. The solution was allowed to stand at roomtemperature for 1 d. The mixture was extracted with water (3×75 mL),resulting in the precipitation of a crystalline solid. The resultingslurry was filtered, and filter cake triturated with ethanol,re-filtered, and dried, affording 29.62 g (73%) of the O-chloracetylamidoxime intermediate. This intermediate was refluxed in xylenes (300mL) for 3 h, and the volatiles removed completely in vacuo, affording25.55 g (72% overall) of the pure 1,2,4-oxadiazole. ¹H NMR (DMSO-d₆) □5.20 (s, 2H), 7.62 (m, 1H), 8.06 (m, 2H), 8.76 (m, 1H). LC-MS (APCI)calcd for C₈H₆ClN₃O: 195.02; found (M+H⁺): 196.0 m/z.

Example B(74)6{2-[3-Chloro-4-(difluoromethoxy)phenyl]ethyl}-6-cyclopentyl-3-[(1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(53), using6{2-[3-chloro-4-(difluoromethoxy)phenyl]ethyl}-6-cyclopentadihydro-2H-pyran-2,4(3H)-dione(from Step 2, below) in place of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.Yield: 1%.

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.75 (m, 8H), 2.03 (m, 2H), 2.11 (s,3H), 2.35 (m, 1H), 2.45-2.60 (m, 3H, overlap with DMSO-d₅), 2.75 (d,J=18.3 Hz, 1H), 3.61 (m, 2H, overlap with H₂O), 3.74 (s, 3H), 7.24 (t,J=73 Hz, overlap with m, combined: 3H), 7.42 (m, 1H). LC-MS (APCI) calcdfor C₂₄H₂₈ClF₂N₃O₄: 495.17; found (M+H⁺): 496.1 m/z.

Step 1: 3-[3-Chloro-4-(difluoromethoxy)phenyl]-1-cyclopentylpropan-1-one

A mixture of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one (15g, 59.35 mmol, Example B(58), Step 2)), methyl2-chloro-2,2-difluoroacetate (17.15 g, 118.7 mmol, 2 equiv) and K₂CO₃(12.4 g, 124.6 mmol, 2.1 equiv) in dry DMF (150 mL) was stirred at75-80° C. for 2 h. The mixture was poured into water and extracted withethyl acetate. The organic layer was washed with aqueous 1 M NaOH andbrine. The organic phase was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was subjected to fractionaldistillation affording 15.3 g (72%) of material that was about 80% pureby ¹H NMR (bp 70° C./2 Torr).

¹H NMR (CDCl₃) δ 1.63 (m, 9H), 2.84 (m, 5H), 6.49 (t, 1H, J=72), 7.11(m, 2H), 7.27 (s, 1H). MS calcd for C₁₅H₁₇F₂O₂Cl, 302.744; found[M-19(—F)]: 283.7 m/z.

Step 2:6-{2-[3-Chloro-4-(difluoromethoxy)phenyl]ethyl}-6-cyclopentadihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared as described in Example B(58), Step 4,using 3-[3-Chloro-4-(difluoromethoxy)phenyl]-1-cyclopentylpropan-1-onein place of3-[3-chloro-4-(cyclopropylmethoxy)phenyl]-1-cyclopentylpropan-1-one,with the exception that the intermediate hydroxy ester was not purified.The residue obtained from the cyclization Step was purified by reversephase column chromatography (C₁₈ stationary phase usingacetonitrile/water/methanol mixture in a polarity gradient). Afterconcentration in vacuo, the residual oil was dissolved in a minimalamount of ethyl ether, and diluted with hexanes. Upon cooling, a whitesolid was obtained. Yield 891 mg (5% overall).

¹H NMR (CDCl₃) δ 1.62(m, 8H), 1.95 (m, 2H), 2.26 (m, 1H), 2.75 (m, 4H),3.42 (s, 2H), 6.84 (m, 3H,), 7.5 (t, 1H, J=7.5). MS calcd forC₁₉H₂₁ClF₂O₄: 386.0; found (M−1): 385.0 m/z.

Example B(75)2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile

To a solution of2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile(0.40 g, 1.1 mmol) from example A(81), in MeOH (7 mL) was added5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g,1.08 mmol, described in Step 3 of example B(75)) from Step 3 below andborane-dimethylamine complex (76 mg, 1.3 mmol) and stirred at roomtemperature for 3 hours. The reaction was quenched with 10 mL saturatedNH₄Cl and 5 mL water. To this was added 20 mL CH₂Cl₂ and the pH of theaqueous phase was adjusted to 3. The layers were separated, and theaqueous layer was extracted with 3×30 mL 10% MeOH in CH₂Cl₂. The organiclayers were combined, and dried over Na₂SO₄. After filtering off thesolids, the liquid was concentrated by rotary evaporation to an oil. Theoil was flash chromatographed, and the resulting product was furtherpurified by preparatory HPLC. Yield: 28 mg, 5%.

MS (ESI): 530 (M−H).

Step 1: (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol

A solution of glycolic acid (70% in water, 70 mL, 805 mmol) was added toaminoguanidine bicarbonate (55.12 g, 405 mmol) carefully. After foamingsubsided, concentrated nitric acid (0.5 mL) was added and the entirereaction was refluxed for 40 hours. The reaction was cooled to 5° C. for30 minutes, and the solids were filtered. The solids were thentriturated with EtOH for 1 hour. The product was then filtered and driedunder nitrogen (40.36 g, 52% yield).

MS (ESI): 115 (M+H).

Step 2: (5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol

To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (9.5 g, 50mmol) from Step 1 above in acetic acid (200 mL) was added2,4-pentanedione (5.13 mL, 50 mmol). The mixture was heated to refluxfor 4 hours, and then cooled to room temperature. The product wasisolated by removing the solvent by rotary evaporation (8.5 g, 95%yield).

MS (ESI): 179 (M+H).

Step 3: 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

A slurry of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol(0.3 g, 1.7 mmol) from Step 2 above and IBX (1.4 g, 5.0 mmol) in1,2-dichloroethane (22 mL) was stirred at 80° C. for 18 hours. Thereaction was cooled to room temperature, and diluted with 100 mL CH₂Cl₂.After the solids were removed by filtration, the solvent was removed byrotary evaporation to give a yellow solid. The solid was purified byflash chromatography to give the desired product (229 mg, 77% yield).

¹H NMR (CDCl₃) δ: 2.72 (s, 3H), 2.86 (s, 3H), 6.96 (s, 1H), 10.24 (s,1H).

Example B(76)1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile

The desired product was prepared analogously to example B(75),substituting1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile(0.24 g, 0.65 mmol) from Example A(86), in place of2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile.Yield: 64 mg, 19%.

¹H NMR (CDCl₃) δ: 1.25-1.30 (m, 2H), 1.42-1.68 (m, 10H), 1.88-1.93 (m,2H), 2.30 (p, J=8.59 Hz, 1H), 2.44-2.73 (m, 10H), 4.05 (d, J=3.03 Hz,2H), 6.76-6.84 (m, 3H), 7.09-7.22 (m, 1H).

Example B(77)3-benzyl-6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

DBU (28.6 ul, 0.191 mmol) was added to a solution of6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(55 mg, 0.174 mmol, described below) in benzene (1.9 ml), under anatmosphere of argon. Benzyl bromide (21 ul, 0.174 mmol) was then added.The reaction mixture was stirred at room temperature for 20 minutes,followed by the addition of 5 crystals of sodium iodide. The reactionmixture was stirred for a further 24 hrs, after which time the mixturewas filtered through a plug of Celite. The filtrate was concentrated invacuo and the residue purified by prep HPLC to afford the title compoundas a white solid (9.0 mg).

¹H NMR (CDCl₃): δ 1.43-1.80 (bm, 8H), 2.20 (m, 2H), 2.24 (m, 1H), 2.72(m, 2H), 3.06 (m, 3H), 3.30 (m, 1H), 3.76 (m, 4H), 6.72 (d, J=8.64 Hz,2H), 6.78 (d, J=8.64 Hz, 2H), 6.94 (m, 3H), 7.23 (m, 2H). Exact Mass:Calcd, 406.51; Found, 406.21.

Step 1:6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

This compound was prepared analogously to Example A(82), where4-Bromo-1-methoxy-benzene was substituted in place of 2-Bromopyridine inStep 1 of that example.

Example B(78) 3-benzyl-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

DBU (28.6 ul, 0.191 mmol) was added to a solution of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(60.6 mg, 0.172 mmol) in benzene (2.0 ml), under an atmosphere of argon.Benzyl bromide (20.5 ul, 0.172 mmol) was then added. The reactionmixture was stirred at room temperature for 20 minutes, followed by theaddition of 5 crystals of sodium iodide. The reaction mixture wasstirred for a further 24 hrs, after which time the mixture was filteredthrough a plug of Celite. The filtrate was concentrated in vacuo and theresidue purified by prep HPLC to afford the title compound as a whitesolid (11.1 mg).

¹H NMR (CDCl₃): δ 1.40-1.90 (bm, 8H), 2.21 (m, 3H), 2.74 (m, 2H), 3.01(t, J=3.10 Hz, 1H), 3.10 (t, J=3.10 Hz, 1H), 3.72 (d, J=2.07 Hz, 1H),3.89 (s, 3H), 6.91 (d, J=2.24 Hz, 1H), 7.17 (m, 3H), 7.30 (m, 4H). ExactMass: Calcd, 440.96; Found, 440.18.

Step 1:{6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

This compound was prepared analogously to Example A(82), where4-Bromo-2-chloro-1-methoxy-benzene was substituted in place of2-Bromopyridine in Step 1 of that example.

¹H NMR (CDCl₃): δ 1.41-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz,1H), 2.61 (t, J=8.6 Hz, 2H), 2.81 (s, 2H), 3.40 (s, 2H), 3.89, (s, 3H),6.45 (d, J=8.5 Hz, 1H), 7.0 (d, J=8.5 Hz, 1H), 7.15 (brs, 1H).

ESIMS (MH+): 351.8.

Example B(79)3-allyl-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(78), whereallyl bromide was substituted in place of benzyl bromide in thatexample.

¹H NMR (CDCl₃): δ 1.44-1.95 (bm, 8H), 2.19 (m, 3H), 2.45 (m, 1H), 2.65(m, 3H), 3.01 (t, J=3.10 Hz, 1H), 3.10 (t, J=2.56 Hz, 2H), 3.14 (m, 1H),3.89 (s, 3H), 5.35 (m, 2H), 6.01 (m, 1H), 6.85 (d, J=1.92 Hz, 1H), 7.17(m, 2H). Exact Mass: Calcd, 390.90; Found, 390.16.

Example B(80)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(pyridin-3-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

DBU (55 ul, 0.367 mmol) was added to a solution of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(58.6 mg, 0.167 mmol) in benzene (16.0 ml) and acetonitrile (3 ml),under an atmosphere of argon. 3-(chloromethyl)pyridine hydrochloride(27.4 mg, 0.167 mmol) was then added. The reaction mixture was stirredat room temperature for 24 hrs, after which time the mixture wasfiltered through a plug of Celite. The filtrate was concentrated invacuo and the residue purified by prep HPLC to afford the title compoundas a white solid (8.60 mg).

¹H NMR (CDCl₃): δ 1.40-1.80 (bm, 8H), 1.90 (m, 2H), 2.30 (m, 1H), 2.51(m, 3H), 2.74 (d, J=17.27 Hz, 1H), 3.74 (m, 3H), 3.85 (s, 3H), 6.73 (d,J=8.32 Hz, 1H), 6.89 (m, 1H), 7.02 (s, 1H), 7.30 (m, 1H), 7.92 (m, 1H),8.26 (s, 1H), 8.55 (s, 1H).

Example B(81)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(pyridin-2-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(80) where2-(chloromethyl)pyridine hydrochloride was substituted in place of3-(chloromethyl)pyridine hydrochloride in that example.

¹H NMR (CDCl₃): δ 1.30-1.80 (bm, 8H), 1.97 (m, 3H), 2.37 (m, 2H), 2.57(m, 3H), 2.69 (s, 1H), 2.75 (s, 1H), 3.87 (s, 3H), 6.83 (d, J=8.32 Hz,1H), 6.97 (d, J=1.92 Hz, 1H), 7.12 (s, 1H), 7.26 (s, 1H), 7.43 (d,J=7.68 Hz, 1H), 7.74 (t, J=7.68 Hz, 1H), 8.40 (d, J=4.80 Hz, 1H). ExactMass: Calcd, 441.95; Found, 441.17.

Example B(82)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(pyridin-4-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(80) where4-(chloromethyl)pyridine hydrochloride was substituted in place of3-(chloromethyl)pyridine hydrochloride in that example.

¹H NMR (CDCl₃): δ 1.25-1.80 (bm, 8H), 1.97 (m, 3H), 2.33 (m, 2H), 2.52(m, 3H), 2.77 (d, J=16.95 Hz, 1H), 3.74 (s, 1H), 3.83 (s, 3H), 6.80 (d,J=8.32 Hz, 1H), 6.93 (m, 1H), 7.06 (s, 1H), 7.39 (bs, 2H), 8.50 (bs,2H).

Example B(83):6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

Potassium carbonate (35.4 mg, 0.256 mmol) was added to a solution of6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(30 mg, 0.085 mmol), 2-(chloromethyl)imidazo[1,2-a]pyrimidine (17.2 mg,0.103 mmol) and sodium iodide (5 crystals) in acetone (40 ml). Thereaction mixture was stirred at reflux for 24 hrs, after which time themixture was acidified to pH=3 and the product was extracted with ethylacetate (3×25 ml). The combined organics were washed with brine (30 ml),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and purified by prep HPLC to afford the titlecompound as a white solid (8.8 mg).

¹H NMR (CDCl₃): δ 1.40-1.88 (bm, 11H), 2.24 (m, 2H), 2.48-2.59 (bm, 3H),3.79 (s, 3H), 4.03 (d, J=14.08 Hz, 1H), 4.18 (d, J=14.08 Hz, 1H), 6.94(d, J=1.60 Hz, 2H), 7.03 (d, J=1.60 Hz, 2H), 8.08 (s, 1H), 8.82 (bs,1H), 8.85 (bs, 1H). Exact Mass: Calcd, 481.97; Found, 481.18.

Example B(84)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-methyl-1H-benzimidazol-2-yl)methyl]dihydro-2H-pyran-2,4(3H)-dione

6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione(127 mg, 0.362 mmol) was dissolved in a mixture of dimethoxy ethyleneglycol (1.8 ml) and water (1.8 ml). The solution was heated to 80° C.Sodium carbonate (42.2 mg, 0.398 mmol) was then added to the mixturefollowed by 2-(chloromethyl)-1-methyl-1H-benzimidazole (42.2 mg, 0.398mmol). The reaction mixture was stirred at 80° C. for 5 hrs, after whichtime the mixture was acidified to pH 5 and the product was extractedwith ethyl acetate (3×25 ml). The combined organics were washed withbrine (30 ml), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo and purified by prep HPLC to affordthe title compound as a white solid (13.5 mg).

¹H NMR (CDCl₃): δ 1.30-1.80 (bm, 11H), 2.22 (m, 1H), 2.50 (t, J=8.29 Hz,2H), 2.92 (d, J=8.10 Hz, 2H), 3.78 (s, 3H), 4.01 (s, 3H), 4.26 (d,J=7.35 Hz, 1H), 6.87 (d, J=2.26 Hz, 1H), 6.90 (s, 1H), 7.00 (d, J=2.07Hz, 2H), 7.44 (m, 3H), 7.54 (m, 1H), 7.84 (m, 1H). Exact Mass: Calcd,495.01; Found, 494.20.

Example B(85)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-(quinolin-2-ylmethyl)dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example B(84), where2-(chloromethyl)quinoline hydrochloride was substituted in place of2-(chloromethyl)-1-methyl-1H-benzimidazole in that example.

¹H NMR (CDCl₃): δ 1.44-1.80 (bm, 8H), 2.20 (m, 3H), 2.72 (m, 2H), 3.01(m, 2H), 3.21 (m, 1H), 3.40 (m, 1H), 3.72 (d, J=4.10 Hz, 1H), 3.89 (s,3H), 6.91 (m, 1H), 7.17 (m, 2H), 7.36 (m, 3H), 7.82 (t, J=8.66 Hz, 2H),8.09 (bs, 1H). Exact Mass: Calcd, 492.01; Found, 491.19.

Example B(86)6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-3-[2-(3-methylisoxazol-5-yl)-acetyl]-5,6-dihydro-pyran-2-one

To a solution of6-cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(52 mg, 0.15 mmol) from Step 2 below, triethylamine (0.075 mL, 0.68mmol) and (3-Methyl-isoxazol-5-yl)-acetic acid (0.027 g, 0.196 mmol) inCH₂Cl₂ (1.5 mL) were added DMAP (1 mg), and EDC (37 mg, 0.196 mmol). Thereaction was stirred at room temperature for 18 hours, and then dilutedwith CH₂Cl₂. The organic was washed with water, and the layers wereseparated. The organic layer was dried under vacuum, and then purifiedby preparatory HPLC to give the desired compound (26.2 mg, 37% yield).

¹H NMR (CDCl₃) δ: 1.47-1.75 (m, 8H), 1.85-1.91 (m, 2H), 2.21 (s, 3H),2.26-2.32 (m, 1H), 2.48-2.53 (m, 2H), 2.71 (d, J=18.09 Hz, 1H), 2.86 (d,J=18.09 Hz, 1H), 3.69 (s, 3H), 3.71 (s, 3H), 4.40-4.57 (m, 2H), 6.00 (s,1H), 6.31-6.36 (m, 2H), 6.91 (d, J=7.91 Hz, 1H).

Step 1: 3-[2-(2,4-dimethoxyphenyl)ethyl]-1-cyclopentylpropan-1-one

A solution of 2,4-dimethoxybenzaldehyde (10.27 g, 45 mmol) and methylcyclopentyl ketone (6.06 g, 54 mmol) in anhydrous ethanol (81 mL) wastreated with 5 M NaOH (aq) (18 mL, 90 mmol) and the mixture stirred atroom temperature for 18 h. The volatiles were removed in vacuo. Theresidue was extracted with ether (100 mL) and the extract washed withwater (3×60 mL), then with brine. The ethereal solution was dried overMgSO₄, filtered, and concentrated in vacuo, affording the intermediatechalcone in a crude yield of 14.63 g. The crude intermediate (14.52 g)was dissolved in 110 mL ethyl acetate, treated with platinum oxide (5mole %) and stirred over 1 atm of H₂ at room temperature overnight. ThePt was filtered through a fine fritted funnel and the black residuewashed with ethyl acetate. The filtrate was concentrated in vacuo togive a yellowish resin. The resin was chromatographed using silica geland 6:1 hexanes/ethyl acetate, yielding 6.02 g (41%) of the ketone as acolorless oil.

¹H NMR (CDCl₃): δ 1.48-1.81 (m, 8H), 2.67 (m, 2H), 2.80 (m, 3H), 3.76(s, 3H), 3.75 (s, 3H), 6.37 (dd, 1H, J=8.1, 2.1 Hz), 6.41 (d, 1H, J=2.1Hz), 7.00 (d, 1H, J=8.1 Hz). MS(APCI) calcd for C₁₆H₂₂O₃: 262.2; found(M+H⁺): 263.1.

Step 2:6-[2-(2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione

Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL)and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) werecarefully added and the reaction mixture was stirred for 20 min. Asolution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was addeddropwise and the resulting mixture was stirred an additional 20 min. Asolution of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one (2.33 g,7.55 mmol) from Step 1 above in THF (37 mL) was added dropwise. Afterstirring 1 h, the reaction mixture was quenched with saturated aq NH₄Cl(100 mL) and extracted with Et₂O (600 mL). The organic phase was driedover MgSO₄ and evaporated. The residue was then stirred overnight in amixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of anaq solution of 10% aq KHSO₄ (50 mL) the resulting mixture was stirred 30min and then extracted with Et₂O (600 mL). The organic phase was washedwith brine, dried over MgSO₄ and evaporated. The residue was purified byflash column chromatography (50% EtOAc in hexanes) to give the product(1.54 g, 52%) as a white foam.

¹H NMR (CDCl₃) δ 1.43 (m, 2H), 1.78 (m, 8H), 2.33 (m, 1H), 2.58 (m, 2H),2.78 (s, 2H), 3.43 (s, 2H), 3.78 (s, 6H), 6.37 (s, 1H), 6.47 (s, 1H),6.93 (d, 1H, J=7.93 Hz).

MS (APCI) calcd for C₂₀H₂₆O₅: 346.2; found (M+1): 347.0.

Example B(87)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(2-pyridin-2-yl-acetyl)-5,6-dihydro-pyran-2-one

The target compound was synthesized analogously to Example B(86),substituting pyridin-2-yl-acetic acid (22 mg, 0.16 mmol) in place of(3-methyl-isoxazol-5-yl)-acetic acid and6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(63 mg, 0.123 mmol) from Step 2 below in place of6-cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.Yield=32 mg, 55% yield.

¹HNMR(CDCl₃)δ: 1.41-1.74 (m, 8H), 1.92-1.98 (m, 2H), 2.40 (p, J=8.00 Hz,1H), 2.56-2.62 (m, 2H), 2.69 (d, J=17.27 Hz, 1H), 2.87 (d, J=17.27 Hz,1H), 3.88 (s, 3H), 4.40 (s, 2H), 6.84 (d, J=8.32 Hz, 1H), 6.96 (d,J=8.32 Hz, 1H), 7.12 (s, 1H), 7.27 (s, 1H), 7.67 (d, J=6.72 Hz, 1H),8.51 (d, J=4.80 Hz, 1H), 8.58 (s, 1H).

Step 1: 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one

To a magnetically stirring solution of 4-bromo-2-chloroanisole (0.50 g,2.61 mmol) and 1-Cyclopentyl-2-propen-1-ol (1.5 eq, 0.49 g, 3.88 mmol)in anhydrous N-methylpyrrolidinone (3.0 mL), under argon at roomtemperature, was added sodium bicarbonate (1.2 eq, 0.26 g, 3.10 mmol)followed by dichlorobis (triphenylphosphine) palladium (II) (0.02 eq,36.7 mg, 0.05 mmol). The resulting mixture was heated to 140° C. in anoil bath and maintained for 4 hours. The resulting dark reaction mixturewas cooled to room temperature and poured into water (50 mL) andextracted with EtOAc (2×25 mL). The organics were washed with water (50mL) and brine (50 mL) then dried over Na₂SO₄, filtered and concentrated.The crude residue was purified by flash chromatography (1% through 10%EtOAc in Hexanes) to yield the intermediate ketone as a slightly yellowoil (0.49 g, 79%).

Step 2:6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example B(86), Step 2substituting 3-(3-chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-onefrom Step 1 above in place of3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one.

¹H NMR (CDCl₃): δ 1.41-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz,1H), 2.61 (t, J=8.6 Hz, 2H), 2.81 (s, 2H), 3.40 (s, 2H), 3.89, (s, 3H),6.45 (d, J=8.5 Hz, 1H), 7.0 (d, J=8.5 Hz, 1H), 7.15 (brs, 1H).

ESIMS (MH+): 351.8.

Example B(88)3-Acetyl-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The target compound was synthesized analogously to Example B(87),substituting acetic acid (0.009 mL, 0.155 mmol) in place ofpyridin-2-yl-acetic acid. Yield=18.4 mg, 38% yield,

¹H NMR (CDCl₃) δ: 1.57-1.77 (m, 8H), 1.94-2.00 (m, 2H), 2.35 (p, J=8.64Hz, 1H), 2.59-2.64 (m, 5H), 2.68-2.90 (m, 2H), 3.87 (s, 3H), 6.84 (d,J=8.32 Hz, 1H), 7.00 (d, J=8.64 Hz, 1H), 7.16 (s, 1H).

Example B(89)7-[(6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl]-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The title compound was prepared as described in Example B(54) where6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione(described in Step 3 of Example B(69)) was used in place of6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 7-(Chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared according to a reported procedure: Doria, G.; Passarotti, C.;Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari,G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) was used inplace of 6-Hydroxy-8-mercaptopurine monohydrate.

¹H NMR (300 MHz, DMSO-D6) δ 1.55 (m, 8H) 1.94 (m, 2H) 2.33 (m, 1H) 2.44(d, J=1.7 Hz, 2H) 2.58 (s, 3H,) 2.58 (1H buried under singlet) 2.71 (d,J=18.0 Hz, 1H) 3.38 (dd, J=15.0, 6.0 Hz, 2H) 5.77 (s, 1H) 6.90 (m, 1H)7.10 (m, 3H) 7.27 (s, 1H) 7.44 (t, J=7.74 Hz, 1H). MS (APCI) calcd forC₂₇H₂₇F₃N₂O₄S: 532.16; found (M+H⁺) 533.0.

Example B(90)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example B(54) where2-(Chloromethyl)imidazo[1,2-a]pyrimidine (described below) was used inplace of 6-Hydroxy-8-mercaptopurine monohydrate with the exception thatit was purified on a Phenomenex Synergi 4u Hydro-RP 21.2 ID×150 mmcolumn using a gradient of A: H₂O/0.05% TFA, B: CAN/0.05% TFA. Thegradient consisted of 5-40% of B for 6 minutes, then 40-70% of B for 9minutes at a flow of 30 mL/min and collection of fractions using UV at260 nm.

¹H NMR (300 MHz, DMSO-D₆) d 1.55 (m, 8H) 1.79 (m, 2H) 2.25 (m, 1H) 2.43(m, 2H) 2.45 (1H, overlapped with DMSO) 2.67 (d, J=17.56 Hz, 1H) 3.60(s, 2H) 3.67 (s, 3H) 3.77 (s, 3H) 6.62 (s, 1H) 6.93 (dd, J=6.80, 4.15Hz, 1H) 7.04 (s, 1H) 7.44 (s, 1H) 8.37 (dd, J=4.15, 1.89 Hz, 1H) 8.77(dd, J=6.80, 1.89 Hz, 1H). MS (APCI) calcd for C₂₇H₃₀ClN₃O₅: 511.19;found (M+H⁺) 512.0.

Step 1: 2-(chloromethyl)imidazo[1,2-a]pyrimidine

A solution of 2-Aminopyridine (19.02 g, 0.2 mol) in anhydrous DME (70mL) was added to 1,3-dichloroacetone (25.39 g, 0.2 mol) to form a slurryin a 250-mL 3-necked round bottomed flask outfitted with a refluxcondenser and a N₂ line. The mixture heated at 65° C. for 18 h, warmedto 80° C. for 3 h and allowed to cool back to room temperature over 2 h.The DME was removed in vacuo and H₂O was added to dissolve the resultingsolid. Saturated NaHCO₃ was added to basify the solution to a pH to 8and ethyl acetate was used to extract the product (3×300 mL). Bothphases were stored in the freezer overnight. The organic phase was driedover Na₂SO₄, filtered and concentrated to give an orange solid. Theaqueous layer was extracted again with ethyl acetate (2×200 mL), thenCH₂Cl₂ (2×200 mL) and these organic layers were dried over Na₂SO₄,filtered and concentrated to an orange solid. The two solids werecombined and dissolved in hot 5-10% MeOH in CH₂Cl₂, and allowed to cool.The resulting orange crystals were filtered and washed with cold CH₂Cl₂.A small amount of ether was added to the mother liquor and scratched andput in the freezer. The resulting solid was filtered cold and washedwith cold ether. The two batches of solid were combined and dried in thevacuum oven to yield 4.93 g (14%) of the desired product.

¹H NMR (CDCl₃) d 4.78 (s, 2H) 6.87 (dd, J=6.6 Hz, J=4.3 Hz, 1H) 7.61 (s,1H) 8.45 (d, J=6.8 Hz 1H) 8.53 (d, J=1.9 Hz, 1H). MS (APCI) calcd forC₇H₆ClN₃: 167.60; found (M+H⁺) 168.0.

Example B(91) 6N-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4,6-dioxotetrahydro-2H-pyran-2-yl}ethyl)-2-ethylphenyl]-N-methylmethanesulfonamide

The title compound was prepared analogously to Example B(31), where{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenyl}-N-methylmethanesulfonamide(described in Example A(87)) was substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein the final step of that example.

¹H NMR (CDCl₃): δ 1.20 (t, J=7.54 Hz, 3H), 1.40-1.80 (brm, 8H), 2.59 (m,2H), 2.62 (m, 2H), 2.67 (m, 5H), 2.79 (m, 5H), 2.95 (m, 5H), 3.20 (m,5H), 6.54 (d, J=2.07 Hz, 1H), 6.95 (s, 1H), 6.98 (d, J=2.07 Hz, 1H),7.07 (m, 1H). Anal. Calcd. For C₃₀H₃₉O₅N₅S: C, 61.94; H, 6.75, N, 12.04.Found: C, 61.64; H, 6.46, N, 12.13.

Example B(92)2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(1-methyl-1H-indol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile

The title compound was prepared analogously to Example B(75), where1-methyl-1H-indole-5-carbaldehyde was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde in thefinal step of that example.

¹H NMR (DMSO-D₆, 300 MHz) δ (ppm): 1.20-1.60 (m, 8H), 1.69 (s, 6H),1.80-1.89 (m, 2H), 2.27-2.36 (m, 1H), 2.45-2.55 (m, 1H), 2.74-2.80 (m,1H), 3.32 (s, 2H), 3.50-3.68 (m, 2H), 3.73 (s, 3H), 6.24 (d, J=3.01 Hz,1H), 6.78 (dd, J=8.10, 0.94 Hz, 1H), 6.95-7.05 (m, 2H), 7.16-7.26 (m,3H), 7.32 (s, 1H). HRMS calcd for C₃₂H₃₆FN₂O₃ (M+H⁺): 512.2705. Found:512.2710.

Example B(93)2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-(1H-pyrazol-4-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile

The title compound was prepared analogously to Example B(75), where1H-pyrazole-4-carbaldehyde was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde in thefinal step of that example.

¹H NMR (300 MHz, DMSO-D₆) δ (ppm) 1.25-1.65 (m, 8H), 1.71 (s, 6H),1.85-1.91 (m, 2H), 2.28-2.35 (m, 1H), 2.54-2.60 (m, 3H), 2.66-2.72 (m,1H), 3.29-3.34 (m, 2H), 6.97 (d, J=8.10 Hz, 1H), 7.08 (dd, J=13.19, 1.13Hz, 1H), 7.35 (m, 3H). Anal. Calcd for C₂₆H₃₀N₃O₃F.0.5H₂O: C, 67.80; H,6.79; N, 9.12. Found: C, 67.98; H, 6.63; N, 9.22.

Example B(94)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-[2-(4-hydroxy-3-isopropyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(4-hydroxy-3-isopropyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Example A(93): ) to5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.23 (t, 6H, J=5.6 Hz), 1.45-1.87 (br m, 8H), 2.14(m, 1H), 2.24 (m, 1H), 2.50-2.71 (m, 10H), 2.88 (d, 1H, J=17.0 Hz), 3.26(m, 1H), 3.84 (d, 1H, J=16.0 Hz), 3.94 (d, 1H, J=16.0 Hz), 6.78 (d, 1H,J=8.1 Hz), 6.94 (d, 1H, J=8.1 Hz), 7.00 (s, 1H), 7.16 (s, 1H), 9.11 (s,1H), 11.00 (br s, 1H). ESIMS: (M+H)⁺505.25.

Example B(95)6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(Example A(95))) to5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.32-1.63 (br m, 8H), 2.02 (m, 2H), 2.34-2.50 (m,10H), 2.72 (d, 1H, J=17.4 Hz), 3.65 (d, 1H, J=16.0 Hz), 3.76 (d, 1H,J=16.0 Hz), 6.81 (d, 1H, J=8.3 Hz), 6.96-6.99 (m, 2H), 7.07 (s, 1H),9.82 (s, 1H), 10.85 (br s, 1H). Anal. Calcd. For C₂₆H₂₉N₄O₄Cl.0.2H₂O: C,62.38; H, 5.92; N, 11.19. Found: C, 62.35; H, 5.96; N, 10.98.

Example B(96)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Example A(96)) to5,7-Dimethyl-[1,2,4]triazolo[1,5-□]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): d 1.06 (t, 3H, J=7.5 Hz), 1.40-1.70 (br m, 8H), 2.08(m, 2H), 2.45-2.54 (m, 12H), 2.76 (d, 1H, J=17.0 Hz), 3.68-3.85 (m, 5H),6.81 (d, 1H, J=8.3 Hz), 6.94 (s, 1H), 7.00-7.04 (m, 2H).

ESIMS: (M+H)⁺505.20.

Example B(97)6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.11 g,0.63 mmol) was added to a solution of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(0.2 g, 0.53 mmol) in MeOH (5 mL). The reaction mixture was stirred for15 mins and then treated with borane-dimethylamine complex (47 mg, 0.80mmoL). After 15 hours the reaction mixture was quenched with 1N HCl andextracted with 10% MeOH in CH₂Cl₂. The combined organic layers wereconcentrated and purified by prep HPLC to give the product (50 mg, 17%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 0.98 (t, J=7.6 Hz, 3H), 1.27-1.59(br m, 8H), 2.00 (m, 2H), 2.33-2.49 (m, 12H), 2.62 (d, J=17.0 Hz, 1H),3.59 (d, J=16.2 Hz, 1H), 3.61 (s, 3H), 3.69 (d, J=16.2 Hz, 1H), 6.91 (s,1H), 6.92 (s, 1H), 7.00 (s, 1H). MS: C₂₉H₃₆N₄O₄Cl (M+H⁺) 539.15.

Step 4: Preparation of Compound6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

Methyl acetoacetate (1.11 mL, 10.2 mmol) was added to a cooled 0° C.suspension of NaH (0.4 g, 10.2 mmol, 60% dispersion in mineral oil) inTHF (15 ml). After 30 min n-BuLi (4.08 mL, 10.2 mmol, 2.5M in hexanes)was added. The resulting dianion was stirred for an additional 30 minand then treated with a solution of3-(3-Chloro-5-ethyl-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.0 g,3.4 mmol) in THF (3 ml). After stirring for 4 h at 0° C., the reactionmixture was quenched with 1N HCl and extracted with EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to ayellow oil that was used without further purification.

The oil was dissolved in methanol (10 mL), treated with potassiumcarbonate (1.4 g, 10.2 mmol), and refluxed under N₂ for 90 min. Thereaction mixture was partitioned between 1N HCl and EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to ayellow oil that was purified by silica gel chromatography (0% to 30%EtOAc in hexanes) to give the title compound as a gum (0.25 g, 20%yield). ¹H NMR (400 MHz, CDCl₃) δ: 1.21 (t, J=7.6 Hz, 3H) 1.42-1.78 (m,8H), 1.92 (m, 2H), 2.27 (m, 1H), 2.57-2.69 (m, 4H), 2.76 (m, 2H), 3.43(s, 2H), 3.81 (s, 3H), 6.85 (s, 1H), 6.99 (s, 1H).

Step 3: Preparation of Compound3-(3-Chloro-5-ethyl-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one

A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol),1-Cyclopentyl-2-propen-1-ol (1.3 g, 10.4 mmol), dichlorobis(triphenylphosphine) palladium (II) (110 mg, 0.16 mmol), and sodiumbicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) washeated to 140° C. under N₂ for 5 h. The reaction mixture was partitionedbetween 1N HCl and EtOAc. The organic layer was washed with saturatedNaHCO₃, brine, dried over Na₂SO₄ and concentrated to black oil. The oilwas purified by flash column chromatography (0% to 10% EtOAc in hexanes)to give the desired product (1.9 g, 82%). ¹H NMR (400 MHz, CDCl₃): δ1.20 (t, J=7.6 Hz, 3H), 1.53-1.81 (m, 8H), 2.65 (q, J=7.6 Hz, 2H), 2.74(m, 2H), 2.79-2.87 (m, 3H), 3.81 (s, 3H), 6.90 (s, 1H), 7.03 (m, 1H).

Step 2: Preparation of Compound5-Bromo-1-chloro-3-ethyl-2-methoxy-benzene

Potassium carbonate (3.9 g, 28 mmol) followed by methyl iodide (0.58 mL,9.3 mmol) were added to a solution of 4-bromo-2-chloro-6-ethyl-phenol(2.2 g, 9.3 mmol) in DMF (10 mL). The mixture was stirred for 20 hoursand then partitioned between 1N HCl and EtOAc. The organic layers werewashed with saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated.The crude yellow oil was purified by flash column chromatography (0% to3% EtOAc in hexanes) to give the desired product (21 g, 91%) ¹H NMR (400MHz, CDCl₃): δ 1.22 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 3.82 (s,3H), 7.22 (s, 1H), 7.37 (s, 1H).

Step 1: Preparation of Compound 4-Bromo-2-chloro-6-ethyl-phenol

Sodium hydroxide (1.2 g, 30 mmol) and hydrazine monohydrate (1.75 mL, 36mmol) were added to a solution of5′-bromo-3′-chloro-2′-hydroxyacetophenone (3 g, 12 mmol) dissolved intriethylene glycol (15 mL). The reaction mixture was heated to 160° C.for 72 hours and then partitioned between 1N HCl and EtOAc. The organiclayer was washed with saturated NaHCO₃, brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash silica gelchromatography (0% to 10% EtOAc in hexanes) to give the title compound(2.34 g, 83%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (t, J=7.6 Hz, 3H), 2.65(q, J=7.6 Hz, 2H), 5.55 (s, 1H), 7.17 (s, 1H), 7.31 (s, 1H).

Example B(98)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where2-bromo-4-ethyl-phenol (from step 1 below) was substituted in place of4-Bromo-2-chloro-6-ethyl-phenol in that example. ¹H NMR (400 MHz,DMSO-d₆) δ: 1.16 (t, J=7.58 Hz, 3H), 1.46-1.77(m, 8H), 2.00 (m, 1H),2.16 (m, 1H), 2.45-2.63 (m, 12H), 2.80 (d, J=17.2 Hz, 1H), 3.71 (s, 3H),3.76 (d, J=16.2 Hz, 1H), 3.86 (d, J=16.4 Hz, 1H), 6.85 (d, J=8.3 Hz,1H), 6.99 (s, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.08 (s, 1H). MS: C₂₉H₃₇N₄O₄(M+H⁺) 505.25.

Step 1: Preparation of Compound 2-Bromo-4-ethyl-phenol

Bromine (11.6 mL, 0.23 mol) was added slowly to a cooled 0° C. of4-ethylphenol (2 g, 0.21 mol) dissolved in CH₂Cl₂ (125 mL). After theaddition was complete the reaction mixture was stirred for 5 mins andthen quenched with 1N NaOH. The reaction mixture was diluted with H₂Oand the layers separated. The organic layer was concentrated to anorange oil. Purification by flash column chromatography (0% to 5% EtOAcin hexanes) gave the title compound as a clear oil (4 g, 98%). ¹H NMR(400 MHz, CDCl₃): δ 1.20 (t, J=7.6 Hz, 3H), 2.58 (q, J=7.5 Hz, 2H), 5.36(s, 1H), 6.93 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.28 (s, 1H).

Example B(99)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(4-ethoxy-3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where4-Bromo-1-ethoxy-2-ethyl-benzene (from step 2 below) was substituted inplace of 5-Bromo-1-chloro-3-ethyl-2-methoxy-benzene in that example. ¹HNMR (400 MHz, DMSO-d₆): δ 0.90 (t, J=7.3 Hz, 3H), 1.16 (t, J=7.1 Hz,3H), 1.23-1.53 (br m, 8H), 1.92 (m, 2H), 2.22-2.42 (m, 12H), 2.64 (d,J=17.4 Hz, 1H), 3.56 (d, J=16.2 Hz, 1H), 3.66 (d, J=16.2 Hz, 1H), 3.82(d, J=7.3 Hz, 2H), 6.63 (d, J=8.3 Hz, 1H), 6.77 (s, 1H), 6.82 (d, J=8.3Hz, 1H), 6.88 (s, 1H), 10.67 (s, 1H). Anal. Calcd. For C₃₀H₃₈N₄O₄: C,68.63; H, 7.30; N 10.67. Found: C, 68.73; H, 7.22; N, 10.60.

Step 2: Preparation of Compound 4-Bromo-1-ethoxy-2-ethyl-benzene

Potassium carbonate (3.3 g, 23.6 mmol) followed by iodoethane (0.63 mL,7.9 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.6 g, 7.9mmol) in DMF (10 mL). The mixture was stirred for 20 hours and thenpartitioned between 1N HCl and EtOAc. The organic layers were washedwith saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated. Thecrude yellow oil was purified by flash column chromatography (hexanes)to give the desired product (1.3 g, 72%).

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, J=7.3 Hz, 3H), 1.41 (t, J=7.1 Hz,3H), 2.60 (q, J=7.6 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 6.68 (d, J=8.1 Hz,1H), 7.24 (m, 2H).

Step 1: Preparation of Compound 4-Bromo-2-ethyl-phenol

A solution of tetrabutyl ammonium tribromide (19.7 g, 41 mmol) in CHCl₃(100 mL) was added to a stirred solution of 2-ethylphenol (5 g, 41 mmol)dissolved in CHCl₃ (150 mL). The reaction mixture was stirred for 2 hrsand then quenched with 5% solution of sodium thiosulfate (150 mL). Thebiphasic mixture was stirred for 30 mins and then the layers wereseparated. The organic layer was washed with 1N HCl, saturated NaHCO₃,brine, dried over Na₂SO₄ and concentrated. The crude residue waspurified by flash column chromatography (0-10% EtOAc in hexanes) to givethe desired product (8.1 g, 98%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (t,J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.64 (d, J=8.5 Hz, 1H), 7.17 (dd,J=8.5, 2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H).

Example B(100)6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(Example 8) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.12 (t, J=7.3 Hz, 3H), 1.46-1.75(m, 8H),2.14 (m, 2H), 2.44-2.64 (m, 12H), 2.83 (d, J=17.4 Hz, 1H), 3.78 (d,J=16.2 Hz, 1H), 3.88 (d, J=16.2 Hz, 1H), 6.94 (s, 1H), 7.05 (s, 1H),7.10 (s, 1H), 6.86 (s, 1H), 10.90 (s, 1H). Anal. Calcd. ForC₂₈H₃₃N₄O₄Cl.H₂O: C, 61.93; H, 6.50; N 10.32. Found: C, 62.02; H, 6.29;N, 10.13.

Example B(101)6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

Trifluoroacetic acid (0.07 mL, 0.88 mmol) was added to a solution of6-{2-[3-Chloro-5-ethyl-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione(0.2 g, 0.44 mmol) dissolved in CH₂Cl₂ (4 mL). The reaction mixture wasstirred for 2 hours at room temperature and then partitioned between H₂Oand EtOAc. The organic extracts were washed with brine, dried overNa₂SO₄ and concentrated to an oil. The oil was purified by flash columnchromatography (0% to 30% EtOAc in hexanes) to give the title compoundas a solid. (0.12 g, 75%). ¹H NMR (400 MHz, CDCl₃): δ 1.21 (t, J=7.6 Hz,3H), 1.58-173 (br m, 8H), 1.92 (m, 2H), 2.26 (m, 1H), 2.57 (m, 2H), 2.65(q, J=7.6 Hz, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 5.47 (s, 1H), 6.81 (s,1H), 6.95 (s, 1H). MS: C₂₀H₂₄O₄Cl (M−H) 363.10.

Step 2: Preparation of Compound6{2-[3-Chloro-5-ethyl-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example B(97) where5-bromo-1-chloro-3-ethyl-2-(2-methoxy-ethoxymethoxy)-benzene (from step1 below) was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in that example. ¹H NMR (400MHz, CDCl₃): δ 1.21 (t, J=7.6 Hz, 3H), 1.32-180 (br m, 8H), 1.92 (m,2H), 2.26 (m, 1H), 2.59 (m, 2H), 2.69 (q, J=7.6 Hz, 2H), 2.76 (s, 2H),3.40 (s, 3H), 3.43 (s, 2H), 3.61 (m, 2H), 3.98 (m, 2H), 5.14 (s, 2H),6.86 (s, 1H), 7.00 (s, 1H).

Step 1: Preparation of Compound5-Bromo-1-chloro-3-ethyl-2-(2-methoxy-ethoxymethoxy)-benzene

A solution of 4-Bromo-2-chloro-6-ethyl-phenol dissolved in THF (10 mL)was added to a cooled 0° C. suspension of NaH (0.43 g, 10.8 mmol, 60%dispersion in mineral oil) in THF (20 ml). After the addition wascomplete the reaction mixture was warmed up to room temperature andstirred for 30 mins. 2-Methoxyethoxymethyl chloride (1.34 mL, 11.7 mmol)was added and the reaction was stirred for 15 hours. The reactionmixture was quenched with 1N HCl and extracted with EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to ayellow oil. Purification by flash column chromatography (0% to 10% EtOAcin hexanes) gave the title compound as a clear oil (2.4 g, 76%). ¹H NMR(400 MHz, CDCl₃): δ 1.21 (t, J=7.3 Hz, 3H), 2.70 (q, J=7.6 Hz, 2H), 3.40(s, 3H), 3.61 (m, 2H), 3.98 (m, 2H), 5.15 (s, 2H), 7.24 (s, 1H), 7.37(s, 1H).

Example B(102)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where4-Bromo-2-ethyl-1-isopropoxy-benzene (from step 1 below) was substitutedin place of 5-Bromo-1-chloro-3-ethyl-2-methoxy-benzene of that example.¹H NMR (400 MHz, DMSO-d₆) δ: 1.00 (t, J=7.6 Hz, 3H), 1.20 (d, J=6.1 Hz,6H), 1.34-1.63(m, 8H), 2.03 (m, 2H), 2.40-2.51 (m, 12H), 2.72 (d, J=17.7Hz, 1H), 3.66 (d, J=16.2 Hz, 1H), 3.77 (d, J=16.2 Hz, 1H), 4.46 (m, 1H),6.76 (d, J=8.3 Hz, 1H) 6.88 (s, 1H), 6.92 (d J=8.1 Hz, 1H), 6.99 (s,1H), 10.81 (s, 1H). MS: C₃₁H₄₀N₄O₄ (M+H⁺) 533.30.

Step 1: Preparation of Compound 4-Bromo-2-ethyl-1-isopropoxy-benzene

Potassium carbonate (3.1 g, 22.4 mmol) followed by 2-iodopropane (0.75mL, 7.5 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.5 g,7.5 mmol) in DMF (10 mL). The mixture was heated at 60° C. for 20 hoursand then partitioned between 1N HCl and EtOAc. The organic layers werewashed with saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated.The crude yellow oil was purified by flash column chromatography(hexanes) to give the desired product (1.35 g, 75%). ¹H NMR (400 MHz,CDCl₃): δ 1.16 (t, J=7.6 Hz, 3H), 1.32 (d, J=6.1 Hz, 6H), 2.58 (q, J=7.6Hz, 2H), 4.49 (m, 1H), 6.70 (d, J=8.6 Hz, 1H), 7.23 (m, 2H).

Example B(103)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where1-Cyclopentyl-3-(2-fluoro-4-methoxy-phenyl)-propan-1-one was substitutedin place of3-(3-chloro-5-ethyl-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one in thatexample. ¹H NMR (400 MHz, DMSO-d₆) δ: 1.16-1.54 (m, 8H), 1.83 (m, 2H),2.20-2.35 (m, 10H), 2.56 (d, J=17.4 Hz, 1H), 3.49 (d, J=16.2 Hz, 1 H),3.51 (s, 3H), 3.59 (d, J=16.2 Hz, 1H), 6.82 (m, 2H), 6.82 (s, 1H), 7.03(t, J=8.6 Hz, 1H), 10.81 (s, 1H). Anal. Calcd. For C₂₇H₃₁N₄O₄F: C,65.57; H, 6.32; N 11.33. Found: C, 65.53; H, 6.34; N, 11.34.

Step 2: Preparation of Compound1-Cyclopentyl-3-(2-fluoro-4-methoxy-phenyl)-propan-1-one

Ba(OH)₂ (0.2 g, 1.2 mmol) was added to a solution of 2-fluoro-4-methoxybenzaldehyde (0.91 g, 5.9 mmol) and 1-Cyclopentyl-ethanone (1 g, 8.9mmol) dissolved in EtOH (10 mL). The reaction mixture was stirredtogether for 20 hours and then partitioned between 1N HCl and EtOAc. Theorganic layer was washed with saturated NaHCO₃, brine, dried over Na₂SO₄and concentrated. Flash column chromatography (0% to 10% EtOAc inhexanes) gave 1-cyclopentyl-3-(2-fluoro-4-methoxy-phenyl)-propenone as ayellow oil contaminated with some unreacted aldehyde.

The crude oil was dissolved in EtOH and 10 wt % Pd/C (0.25 g, Degussatype) was added. The mixture was stirred under a balloon of H₂ for 30mins and then filtered through a pad of celite washing with EtOAc. Thefiltrate was concentrated and purified by flash column chromatography(0% to 20% EtOAc in hexanes) to give the title compound as an oil (0.57g, 39%). ¹H NMR (400 MHz, CDCl₃): δ 1.53-1.80 (m, 8H), 2.73 (m, 2H),2.84 (m, 3H), 3.77 (s, 3H), 6.56-6.62 (m, 2H), 7.08 (t, 1H).

Step 1: Preparation of Compound 1-Cyclopentyl-ethanone

Cyclopentylmagnesium bromide (250 mL, 0.5 mol, 2M sol in THF) was addedto a cooled −78° C. solution of acetic anhydride (39 mL, 0.42 mol)dissolved in THF (100 mL). The reaction mixture was stirred for 2 hours.The reaction was quenched with saturated NH₄Cl and extracted with ether.The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a black oil. Vacuum distillation gave the product as ayellow oil (16 g, 33% yield) ¹H NMR (CDCl₃): δ 1.55-1.84 (br m, 8H),2.16 (s, 3H), 2.87 (m, 1H).

Example B(104)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

This compound was prepared analogously to example C(112), except that6-Cyclopentyl-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dionewas used in place of2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrileThe result was a white solid. ¹H NMR (300 MHz, CDCl₃): δ: 1.20 (t, J=7.5Hz, 3H), 1.52-1.81 (m, 9H), 2.04 (m, 2H), 2.39 (m, 1H), 2.62 (m, 10H),2.79 (s, 3H), 4.05 (d, J=15.5 Hz, 1H), 4.25 (m, 4H), 4.12 (d, J=15.5 Hz,1H), 6.84 (s, 1H), 6.98 (m, 3H).

Example B(105):6-Cyclopentyl-3-(5,7-dimethyl-1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

This compound was prepared analogously to example C(112), except that6-Cyclopentyl-6-[2-(3-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas used in place of2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile.The result was a white solid. ¹H NMR (CDCl₃): δ: 1.44-1.92 (brm, 8H),2.05 (m, 2H), 2.35 (m, 1H) 2.44-2.88 (m, 11H), 4.05 (s, 2H), 6.85 (s,1H), 6.99 (m, 2H), 7.15 (d, J=7.5 Hz, 1H).

Example B(106)[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenoxy]acetonitrile

The title compound was prepared analogously to Example A(131), where{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenoxy}acetonitrile(from step 3 below) was substituted in place of6-cyclopentyl-6-[2-(3-fluoro-4-{methyl[methyl(dimethylene)-6-sulfanyl]amino}phenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione. ¹H NMR (CDCl₃): δ 1.40-2.24 (brm,7H), 2.0-2.18 (m, 5H), 2.63 (s, 3H); 2.74 (m, 5H), 3.20 (m, 2H), 4.00(s,2H); 4.74 (s, 2H); 6.77-7.10 (m, 4H).

Step 3:{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenoxy}acetonitrile

Methyl acetoacetate (3.2 mL, 29.4 mmol) was added to a cooled 0° C.suspension of NaH (1.17 g, 29.4 mmol, 60% dispersion in mineral oil) inTHF (50 ml). After 30 min n-BuLi (11.7 mL, 29.4 mmol, 2.5M in hexanes)was added. The resulting dianion was stirred for an additional 30 minand then treated with a solution of[4-(3-Cyclopentyl-3-oxo-propyl)-2-fluoro-phenoxy]-acetonitrile (2.7 g,9.8 mmol) in THF (30 ml). After stirring for 4 h at 0° C., the reactionmixture was quenched with 1N HCl and extracted with EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to ayellow oil that was used without further purification.

The oil was dissolved in toluene (10 mL) and treated with Otera catalyst(100 mg). The reaction mixture was heated to 80° C. under N₂ for 30 min.The reaction mixture was concentrated and crystallized from CH₂Cl₂ togive the title compound (0.2 g, 24% yield). MS (APCI): 358 (M−H).

Step 2: [4-(3-Cyclopentyl-3-oxo-propyl)-2-fluoro-phenoxy]-acetonitrile

A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol),1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis(triphenylphosphine) palladium (II) (151 mg, 0.22 mmol), and sodiumbicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) washeated to 140° C. under N₂ for 5 hours. The reaction mixture waspartitioned between 1N HCl and EtOAc. The organic layer was washed withsaturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to a blackoil. The oil was purified by flash column chromatography (Hexanes to 10%EtOAc in hexanes) to give the desired product (2.7 g, 93%). ¹H NMR(CDCl₃): δ 1.52-1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H),6.92-7.06 (m, 3H).

Step 1: Preparation of (4-bromo-2-fluorophenoxy)acetonitrile

Bromoacetonitrile (1.81 ml, 0.026M) was added to a solution of4-bromo-2-fluorophenol (5.0 g, 0.026M) and potassium carbonate (3.54 g,0.026M) in DMF (50 ml). The reaction was stirred for 12 hours and thenpartitioned between diethyl ether (200 ml) and water (200 ml). Theorganics were separated, dried over magnesium sulfate, filtered andconcentrated in vacuuo to afford the title compound as a yellow oil (6.0g). ¹H NMR (CDCl₃): δ 4.84 (s, 2H), 7.03-7.10 (m, 2H), 7.21 (m, 1H).

Example B(107)6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

This compound was prepared analogously to example C (112), except that6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dionewas used in place of2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrileThe result was a white solid. ¹H NMR (300 MHz, CDCl₃): δ: 0.61 (m, 2H),0.88 (m, 2H), 1.55 (m, 8H), 1.97 (m, 2H), 2.11 (m, 1H), 2.36 (m, 1H),2.57 (m, 5H), 2.67 (s, 3H), 2.79 (s, 3H), 3.82 (s, 3H), 4.08(m, 2H),6.59 (s, 1H), 6.73 (d, J=8.3 Hz, 1H), 6.84 (s, 1H), 6.89 (d, J=8.3 Hz,1H).

Example B(108)6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example B(97), where5-Bromo-1,3-dichloro-2-ethoxy-benzene was substituted in place of5-Bromo-1-chloro-3-ethyl-2-methoxy-benzene. ¹H NMR (400 MHz, CDCl₃): δ1.45 (t, J=7.0 Hz, 3H), 1.49-1.76 (m, 8H), 1.87-1.98 (m, 2H), 2.22-2.31(m, 1H), 2.57-2.64 (m, 2H), 2.75 (d, J=6 Hz, 2H), 3.44 (s, 2H), 4.07 (q,J=7 Hz, 2H), 7.07 (s, 2H). ESIMS (M+H)⁺:400.

Step 1: 4-bromo-2,6-dichlorophenyl Ethyl Ether

The title compound was prepared analogously to step 2 in Example A(125),where 5-Bromo-1,3-dichloro-phenol was substituted in place of4-bromo-2-ethyl-phenol in that example.

¹H NMR (400 MHz, CDCl₃): δ 1.46 (t, J=7.0 Hz, 3H), 4.10 (q, J=7 Hz, 2H),7.09 (s, 2H).

Example B(109)4-{3-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-propionylamino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously to Example B(97), where4-(4-Cyclopentyl-4-oxo-butyrylamino)-piperidine-1-carboxylic acidtert-butyl ester (from step 2 below) was substituted in place of3-(3-chloro-5-ethyl-4-methoxy-phenyl)-1-cyclopentyl-propa-1-one in step4 of that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.34 (s, 9H), 1.35-1.61(m, 18H), 1.97-2.15 (m, 4H), 2.49 (s, 3H), 2.59 (s, 3H), 3.64-3.76 (m,5H), 7.03 (s, 1H), 7.79 (d, J=7.5, 1H).

ESIMS (M+H)⁺: 597.

Step 2: 4-(4-Cyclopentyl-4-oxo-butyrylamino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

The title compound was prepared analogously to step 4 from ExampleB(97), where4-(4-Cyclopentyl-4-oxo-butyrylamino)-piperidine-1-carboxylic acidtert-butyl ester (described in step 1 below) was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of that example. ¹HNMR (400 MHz, DMSO-d₆): δ 1.24-1.42 (m, 8H), 1.45 (s, 9H), 1.59-2.32 (m,4H), 2.62 (d, J=16 Hz, 1H), 2.71 (d, J=16 Hz, 1H), 2.80-2.84 (s, 9H),3.39 (d, J=18 Hz, 1H), 3.56 (d, J=18 Hz, 1H), 3.86 (m, 2H). MS(ESI):435(MH−).

Step 1: 4-(4-Cyclopentyl-4-oxo-butyrylamino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

To a stirred solution of 4-Amino-piperidine-1-carboxylic acid tert-butylester (0.3 g, 1.49 mmol) in anhydrous CH₂Cl₂ under argon and cooled to0° C., were added 4-Cyclopentyl-4-oxo-butyric acid (0.31 g, 1.79 mmol),EDC.HCl (0.35 g, 1.79 mmol), HOBt (0.24 g, 1.79 mmol), and TEA (0.25 mL,1.79 mmol). The resulting solution was stirred at 25° C. overnight.CH₂Cl₂ was evaporate and the residue was partitioned between EtOAc and1N HCl. The organic layer was washed with H₂O, brine and dried overNa₂SO₄. The solvent was removed in vacuo and the residue was purified byflash column chromatography (80% EtOAc in hexanes) to provide thedesired product (0.37 g, 71%) as a white solid. ¹H NMR (400 MHz, CDCl₃):δ 1.24-1.32 (m, 2H), 1.45 (s, 9H), 1.60-1.85 (m, 11H), 2.41 (t, J=6.4Hz, 2H), 2.79-3.04 (m, 5H), 3.85-4.13 (m, 2H), 5.65 (s, 1H). MS(ESI):351(MH−).

Example B(110)6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(5-methyl-1H-imidazol-4-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(126), where4-methyl-5-imidazol carboxaldehyde was substituted in place of6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of thatexample. ¹H NMR (400 MHz, DMSO-d₆): δ 1.09 (t, J=7.4 Hz, 3H), 1.30-1.60(m, 8H), 1.80-1.85 (m, 2H), 2.09 (s, 3H), 2.22-2.31 (m, 1H), 2.38-2.57(m, 5H), 2.71 (d, J=16 Hz, 1H), 3.46 (m, 2H), 6.64-6.72 (m, 3H), 6.79(s, 1H), 8.43 (s, 1H). Anal. Calcd. For C₂₅H₃₂N₂O₄-1 HCl.0.25H₂O: C,64.51; H, 7.25; N, 6.02. Found: C, 64.22; H, 7.31; N, 5.91.MS(ESI):425.2 (M+H)⁺.

Example B(111)6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-3-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(30), where2-ethyl-5-formyl-4-methylimidazole carboxaldehyde was substituted inplace of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde ofthat example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.15 (t, J=7.4 Hz, 3H), 1.25(t, J=7.6 Hz, 3H), 1.40-1.75 (m, 8H), 1.80-1.9 (m, 2H), 2.17 (s, 3H),2.25-2.35 (m, 1H), 2.44-2.64 (m, 6H), 2.74 (q, J=7.4 Hz, 2H), 3.46 (d,J=4.5 Hz, 2H), 6.70-6.81 (m, 3H), 6.87 (s, 1H). Anal. Calcd. ForC₂₇H₃₆N₂O₄.1H₂O: C, 68.91; H, 8.14; N, 5.95. Found: C, 69.89; H, 7.91;N, 6.05. MS(ESI):453.2 (MH+).

Example B(112)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-{2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where6-Cyclopentyl-6-{2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(from step 2 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.17 (d, J=6.4 Hz, 3H),1.37-1.56 (m, 8H), 1.96-2 (m, 2H), 2.35-2.44 (m, 10H), 2.67 (d, J=17 Hz,1H), 3.59 (d, J=16 Hz, 1H), 3.71 (d, J=16 Hz, 1H), 4.504.55 (m, 1H),4.93 (d, J=4.1 Hz, 1H), 6.92 (s, 1H), 7.03 (d, J=8.1 Hz, 2H), 7.10 (d,J=8.1 Hz, 2H), 10.73 (brs, 1H). Anal. Calcd. For C₂₈H₃₄N₄O₄: C, 68.55;H, 6.99; N, 11.42. Found: C, 68.70; H, 7.10; N, 11.52. MS(ESI):491.2(M+H)⁺.

Step 2:6-Cyclopentyl-6-{2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from ExampleB(97), where (R)1-(4-Bromo-phenyl)-ethanol (described in step 1 below)was substituted in place of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzenein step 3 of that example. ¹H NMR (400 MHz, CDCl₃): δ 1.48 (d, J=6.4 Hz,3H), 1.52-1.79 (m, 8H), 1.95 (q, J=17, 8.5 Hz, 2H), 2.26-2.32 (m, 1H),2.68 (t, J=8.5 Hz, 2H), 2.78 (s, 2H), 3.42 (s, 2H), 4.88 (q, J=13, 6.4Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H). Anal. Calcd.For C₂₀H₂₆O₄.0.5H₂O: C, 70.77; H, 8.02. Found: C, 70.37; H, 7.95. ESIMS(MH−): 329.

Step 1: (R)1-(4-Bromo-phenyl)-ethanol

The title compound was prepared as described in the following reference:Tetrahedron 2001, 57, 5027-5038.

Example B(113)6-[2-(4-Chloro-3-ethyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where4-bromo-1-chloro-2-ethyl-benzene (from step 4 below) was substituted inplace of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of thatexample. ¹H NMR (400 MHz, DMSO-d₆): δ 1.21 (t, J=7.3 Hz, 3H), 1.49-1.80(br m, 8H), 2.22 (m, 2H), 2.54-2.77 (m, 12H), 2.87 (d, J=17.7 Hz, 1H),3.80 (d, J=16.0 Hz, 1H), 3.93 (d, J=16.1 Hz, 1H), 7.15 (s, 1H), 7.22(dd, J=8.1, 2.0 Hz, 1H), 7.27 (s, 1H), 7.38 (d, J=8.1 Hz, 1H). Anal.Calcd. For C₂₈H₃₃N₄O₃.0.5H₂O: C, 64.91; H, 6.62; N 10.82. Found: C,64.93; H, 6.59; N, 10.50.

Step 4: 4-Bromo-1-chloro-2-ethyl-benzene

Sodium hydroxide (0.39 g, 9.6 mmol) and hydrazine monohydrate (0.56 mL,11.5 mmol) were added to a solution of1-(5-Bromo-2-chloro-phenyl)-ethanone (0.9 g, 3.85 mmol) dissolved intriethylene glycol (5 mL). The reaction mixture was heated to 170° C.for 24 hours and then partitioned between 1N HCl and EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash silica gel chromatography (0% to 5% EtOAcin hexanes) to give the title compound (0.52 g, 62%). ¹H NMR (400 MHz,CDCl₃): δ 1.23 (t, J=7.6 Hz, 3H), 2.72 (q, J=7.6 Hz, 2H), 7.19 (d, J=8.6Hz, 1H), 7.25 (dd, J=8.3, 2.3 Hz, 1H), 7.36 (d, J=2.5 Hz, 1H).

Step 3: 1-(5-Bromo-2-chloro-phenyl)-ethanone

Pyridinium dichromate (2.6 g, 6.94 mmol) was added to a solution of1-(5-bromo-2-chloro-phenyl)-ethanol (1.09 g, 4.6 mmol) in CH₂Cl₂ (20mL). The reaction was stirred for 15 hours and then more pyridiniumdichromate (2.6 g, 6.94 mmol) was added. After another 24 hours celitewas added and the mixture was stirred for 20 mins. The reaction mixturewas filtered through a pad of celite washing with ether. The filtratewas concentrated to a brown oil. The residue was purified by flashsilica gel chromatography (0% to 10% EtOAc in hexanes) to give the titlecompound as a clear oil (0.92 g, 85%). ¹H NMR (400 MHz, CDCl₃): δ 2.64(s, 3H), 7.29 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H).

Step 2: 1-(5-Bromo-2-chloro-phenyl)-ethanol

Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled−78° C. solution of 5-bromo-2-chloro-benzaldehyde (2.75 g, 12.5 mmol)dissolved in THF (40 mL). The reaction mixture was stirred for 15 hoursand then quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic extracts were washed with 1N HCl, brine, dried over Na₂SO₄ andconcentrated to an oil. The oil was purified by flash columnchromatography (0% to 10% EtOAc in hexanes) to give the title compoundas a solid (2.63 g, 91%). ¹H NMR (400 MHz, CDCl₃): δ 6.32 (d, J=6.3 Hz,3H), 2.00 (d, J=3.8 Hz, 1H), 5.24 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.33(dd, J=8.6, 2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H).

Step 1: 5-Bromo-2-chloro-benzaldehyde

Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH₂Cl₂ (30 mL). Thereaction was stirred for 5 hours and then celite was added. The mixturewas stirred for 20 mins and then filtered through a pad of celitewashing with ether. The filtrate was concentrated to a brown oil. Theresidue was purified by flash silica gel chromatography (0% to 10% EtOAcin hexanes) to give the title compound as a clear oil (1.28 g, 86%). ¹HNMR (400 MHz, CDCl₃): δ 7.35 (d, J=8.6 Hz, 1H), 7.65 (dd, J=8.3, 2.5 Hz,1H), 8.04 (d, J=2.5 Hz, 1H), 10.41 (s, 1H).

Example B(114)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where6-Cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(from step 4 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.41 (d, J=6.4 Hz, 3H),1.57-1.8 (m, 8H), 2.20-2.25 (m, 2H), 2.58-2.74 (m, 10H), 2.90 (d, J=17Hz, 1H), 3.82 (d, J=16 Hz, 1H), 3.94 (d, J=16 Hz, 1H), 5.0-5.08 (m, 1H),5.29-5.33 (m, 1H), 7.06 (d, J=11.5 Hz, 1H), 7.16 (s, 1H), 7.19 (d,J=7.70 Hz, 1H), 7.50-7.56 (m, 1H), 11.0 (s, 1H). Anal. Calcd. ForC₂₈H₃₃N₄O₄F.0.25H₂O: C, 65.54; H, 6.58; N, 10.92. Found: C, 65.47; H,6.56; N, 10.73. MS(ESI): 508.2 (M+H)⁺.

Example B(115)6-Cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from ExampleB(97), where (R) 1-(4-Bromo-2-fluoro-phenyl)-ethanol (described in step3 below) was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of that example. ¹HNMR (400 MHz, CDCl₃): δ 1.50 (d, J=6.4 Hz, 3H), 1.52-1.88 (m, 8H),1.91-1.98 (m, 2H), 2.22-2.32 (m, 1H), 2.64-2.69 (m, 2H), 2.77 (s, 2H),3.43 (s, 2H), 5.16 (q, J=13, 6.4 Hz, 1H), 6.82 (dd, J=11, 1.5 Hz, 1H),6.94 (dd, J=7.9, 1.5 Hz, 1H), 7.4 (t, J=7.9 Hz, 1H). Anal. Calcd. ForC₂₀H₂₅FO₄.0.5H₂O: C, 67.21; H. 7.33. Found: C, 67.15; H, 7.14. ESIMS(MH−): 349.

Step 3: (R) 1-(4-Bromo-2-fluoro-phenyl)-ethanol

An oven dried 500 mL flask, was charged under nitrogen with(S)-2-methyl-CBS-oxazaborolidine 1M in toluene (5.02 mL) and dissolvedin CH₂Cl₂ (250 mL). Me₂-BH₃ (30 mL, 60.27 mmol) was then added andcooled to −30° C. and reaction stirred for 15 minutes.(1-(4-Bromo-2-fluoro-phenyl)-ethanone (10.9 g, 50.23 mmol) from step 2below was dissolved in CH₂Cl₂ (10 mL) and slowly added via additionfunnel to the previous solution. The resulting reaction was stirred at25° C. overnight. The solution was carefully quenched with MeOH, thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography (20% EtOAc in hexanes) to provide the desiredproduct (9 37 g, 90%) as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ 1.49(d, J=6.6 Hz, 3H), 5.15 (q, J=12, 6.4 Hz, 1H), 7.15-7.45 (m, 3H).

Step 2: 1-(4-Bromo-2-fluoro-phenyl)-ethanone

4-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester (39 g, 124.94mmol) from step 1 below was dissolved in THF (500 mL) and cooled to −78°C. MeMgBr 3.0 M solution (45 mL, 137.43 mmol) was added and reactionstirred 1 hour at −78° C. The resulting reaction mixture was poured intoNaHCO₃ (100 mL) and extracted with EtOAC. The combined organics werewashed with water (100 mL) and brine (100 mL) then dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by flashchromatography (10% EtOAc in Hexanes) to yield the intermediate ketoneas a colorless oil (20 g, 74%). ¹H NMR (CDCl₃): δ 2.63 (d, 3H, J=5.1 Hz,3H), 7.37 (dd, J=8.8, 1.9 Hz, 1H), 7.37 (s, 1H), 7.77 (7, J=8.8 Hz, 1H).ESIMS (MH+): 218.2.

Step 1: -Bromo-2-fluoro-thiobenzoic Acid S-pyridin-2-yl Ester

Aldrithiol-2 (30.18 g, 137 mmol followed by triphenylphosphine (36 g,137 mmol were added to a solution of 4-bromo-2-fluorobenzoic acid (25 g,114.16 mmol in CH₂CL₂ (570 mL) cooled to 0° C. The resulting mixture wasstirred 4 hours at room temperature. The CH₂Cl₂ was then evaporated andresidue was purified by flash column chromatography (20% EtOAc inhexanes) to give the product (35 g, 100%) as a pale yellow oil). ¹H NMR(CDCl₃) δ 7.33-7.44 (m, 3H), 7.71-7.83 (m, 3H), 8.67-8.71 (m, 1H). ESIMS(MH+): 313.1.

Example B(116)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where where6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehydeand6-Cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(Example B(115) (was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example.

¹H NMR (400 MHz, DMSO-d₆): δ 1.13 (d, J=6.4 Hz, 3H), 1.23-1.60 (m, 8H),1.81-1.91 (m, 2H), 2.21-2.25 (m, 1H), 2.40-2.46 (m 3H), 2.6 (d, J=16 Hz,1H), 3.14 (s, 1H), 3.58 (d, J=16 Hz, 1H), 3.68 (d, J=16 Hz, 1H),4.78-4.80 (m, 1H), 5.02 (d, J=5 Hz, 1H), 6.75 (d, J=10 Hz, 1H), 6.85 (d,J=7.7 Hz, 1H), 7.23 (t, J=7.70 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H), 9.4 (d,J=2.5 Hz, 1H). Anal. Calcd. For C₂₆H₂₈ClFN₄O₄.0.5H₂O: C, 59.60; H, 5.58;N, 10.69. Found: C, 59.67; H, 5.44; N, 10.65. MS (ESI): 515.2 (M+H)⁺.

Example B(117)6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where1-Bromo-2,4-dimethoxy-benzene was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of that example. ¹HNMR (400 MHz, DMSO-d₆): δ 1.52-1.89 (m, 8H), 2.06-2.26 (m, 3H),2.59-2.70 (m, 9H), 2.95 (d, J=16 Hz, 1H), 3.49 (s, 2H), 3.82 (s, 3H),3.88 (s, 3H), 6.55-6.62 (m, 2H), 7.18-7.21 (m, 2H), 11 (s, 1H). Anal.Calcd. For C₂₈H₃₄N₄O₅: C, 66.39; H, 6.76; N, 11.06. Found: C, 66.18; H,6.76; N, 10.74. MS (ESI): 507 (M+H)⁺.

Example B(118)6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehydeand6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-onewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.36-1.72 (m, 8H),1.93-2.02 (m, 2H), 2.35 (s, 3H), 2.42-2.58 (m, 2H), 2.76 (d, J=16 Hz,1H), 3.34 (s, 6H), 3.69 (s, 2H), 3.73 (s, 2H), 6.46 (dd, J=8, 2.5 Hz,1H), 6.49 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.70 (d, J=2.5 Hz,1H), 8.85-8.87 (m, 1H), 10.8 (s, 1H). Anal. Calcd. For C₂₇H₃₂N₄O₅:0.1H₂O: C, 63.51; H, 6.71; N, 10.97. Found: C, 63.50; H, 6.70; N, 10.87.MS (ESI): 493 (M+H)⁺.

Example B(119)3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97), where6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substitutedin place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehydeand6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-onewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.51-1.73 (m, 9H),1.92-1.98 (m, 2H), 2.38-2.58 (m, 3H), 2.79 (d, J=16 Hz, 1H), 3.71 (s,2H), 3.73 (s, 6H), 6.40-6.5 (m, 2H), 7.03 (d, J=8 Hz, 1H), 8.89 (d,J=2.6 Hz, 1H), 9.52 (d, J=2.6 Hz, 1H), 10.9 (s, 1H). Anal. Calcd. ForC₂₆H₂₉ClN₄O₅.0.25H₂O: C, 60.35; H, 5.75; N, 10.83. Found: C, 60.40; H,5.65; N, 10.74. MS (ESI): 513 (M+H)⁺.

Example B(120)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-{2-[3-(1-hydroxy-ethyl)-4-methoxy-phenyl]-ethyl}-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) where6-Cyclopentyl-6-{2-[3-(1-hydroxy-ethyl)-4-methoxy-phenyl]-ethyl}-dihydro-pyran-2,4-dione(from step 2 below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18-1.24 (m, 3H),1.37-1.74 (m, 8H), 2.00-2.2 (m, 2H), 2.4-2.83 (m, 9H), 3.75 (s, 3H),3.75-3.85 (m, 2H), 4.63 (d, J=6 Hz, 1H), 4.93 9 (s, 2H), 6.82 (d, J=8.3Hz, 1H), 7.05-7.07 (m, 3H), 7.25 (s, 1H), 16.9 (s, 1H). MS (ESI): 521.2(M+H)⁺.

Example B(121)6-Cyclopentyl-6{2-[3-(1-hydroxy-ethyl)-4-methoxy-phenyl]-ethyl}-dihydro-pyran-2,4-dione(

The title compound was prepared analogously to step 4 from Example B(97)where (R) 1-(5-Bromo-2-methoxy-phenyl)-ethanol (described in step 1below) was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of that example. ¹HNMR (400 MHz, CDCl₃): δ 1.6-2.28 (m, 16H), 2.6-2.69 (m, 2H), 2.74 (d,J=7.6 Hz, 2H), 3.41 (d, J=4.8 Hz, 2H), 3.70-3.71 (m, 1H), 3.84 (s, 2H),6.80 (d, J=8.9, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.12 (s, 1H). ESIMS (MH−):361.2.

Step 1: (R) 1-(5-Bromo-2-methoxy-phenyl)-ethanol

An oven dried 500 mL flask, was charged under nitrogen with(S)-2-methyl-CBS-oxazaborolidine 1M in toluene (2.18 mL) and dissolvedin CH₂Cl₂ (100 mL). Me₂—BH₃ (13.10 mL, 26.20 mmol) was then added andcooled reaction to −30° C. then stirred for 15 minutes.5-Bromo-2-methoxyacetophenone (5 g, 21.83 mmol) was dissolved in CH₂Cl₂(10 mL) and slowly added via addition funnel to the previous solution.The resulting reaction was stirred at −30° C. for 1 hour. The solutionwas carefully quenched with MeOH, the solvent was removed in vacuo andthe residue was purified by flash column chromatography (20% EtOAc inhexanes) to provide the desired product (5 g, 100%) as a clear oil. ¹HNMR (400 MHz, CDCl₃): δ 1.47 (d, J=6.41 Hz, 3H), 2.44 (d, J=5 Hz, 1H),3.84 (s, 3H), 5.03-5.11 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 7.33 (dd,J=8.7, 2.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H).

Example B(122)6-{2-[3-Chloro-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example B(97) whereExample B(123)(6-Cyclopentyl-6{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione(below) was substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dioneof that example. ¹H NMR (400 MHz, DMSO-d₆): δ 1.5-1.7 (m, 9H) 2.20-2.22(m, 2H), 2.49-2.90 (m, 10H), 3.39 (s, 3H), 3.70-3.74 (m, 2H), 3.78 (d,J=16 Hz, 1H), 3.90 (d, J=16 Hz, 1H), 4.04-4.07 (m, 2H), 7.13 (s, 1H),7.32 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 10.9 (s, 1H).Anal. Calcd. For C₃₀H₃₅ClN₄O₅: C, 63.54; H, 6.22; N, 9.88. Found: C,63.27; H, 6.27; N, 9.56. MS (ESI): 567.2 (M+H)⁺.

Example B(123)6-{2-[3-Chloro-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to step 4 from Example B(97)where 2-(4-Bromo-2-chloro-phenyl)-2-methyl-[1,3]dioxolane (described instep 3 below) was substituted in place of5-bromo-1-chloro-3-ethyl-2-methoxy-benzene in step 3 of that example. ¹HNMR (CDCl₃-d₆): δ 1.57-1.73 (m, 8H), 1.78 (s, 3H), 1.91-1.98 (m, 2H),2.2-2.3 (m, 1H), 2.62-2.68 (m, 2H), 2.77 (d, J=2.2 Hz, 2H), 3.43 (s,2H), 3.75-3.79 (m, 2H), 4.044.09 (m, 2H), 7.01 (dd, J=7.9, 1.8 Hz, 1H),7.17 (d, J=1.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H). ESIMS (MNa+): 429.1.

Step 3: 2-(4-Bromo-2-chloro-phenyl)-2-methyl-[1,3]dioxolane

1-(4-Bromo-2-chloro-phenyl)-ethanone (from step 2 below) (1.86 g, 5.66mmol), below was dissolved in ethylene glycol (5 mL).Triethylorthoformate (0.71 g, 4.79 mmol), and tosic acid (0.02 g) wereadded and reaction was stirred under nitrogen for 24 hours at roomtemperature. The resulting reaction mixture was poured into NaHCO₃ (10mL) and extracted with EtOAC. The combined organics were washed withwater (10 mL) and brine (10 mL) then dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by flash chromatography (5%EtOAc in Hexanes) to yield the intermediate ether as a colorless oil(0.69 g, 58%). ¹H NMR (CDCl₃): δ 1.77 (s, 3H), 3.74-3.79 (m, 2H),4.04-4.09 (m, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H),7.55 (d, J=1.9 Hz, 1H). ESIMS (MH+): 278.2.

Step 2: 1-(4-Bromo-2-chloro-phenyl)-ethanone

The title compound was prepared analogously to Step 2 from Example X(X):6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-onewhere 4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (describedin step 1 below) was substituted in place of4-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester. ¹H NMR (CDCl₃) δ2.64 (s, 3H), 7.46-7.48 (m, 2H), 7.61 (s, 1H). ESIMS (MH+): 234.1.

Step 1: 4-Bromo-2-chloro-thiobenzoic Acid S-pyridin-2-yl Ester

The title compound was prepared analogously to Step 1 from Example X(X):6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-onewhere 4-bromo-2-chlorobenzoic acid was substituted in place of4-bromo-2-fluorobenzoic acid of that example. ¹H NMR (CDCl₃) δ 7.34-7.38(m, 1H), 7.53 (dd, J=8.3, 1.7 Hz, 1H), 7.67-7.85 (m, 4H), 8.68 (d, J=5.6Hz, 1H). ESIMS (MH+): 329.1.

Example B(124)6-[2-(4-Acetyl-3-chloro-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared in the following way: Example B(122)6-{2-[3-Chloro-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one(0.138 g, 0.24 mmol), was dissolved in acetone (8 mL). Amberlyst-13(0.23 g) was added from top and reaction was stirred under nitrogen for72 hours at room temperature. The resulting reaction mixture wasfiltered through fritted funnel to remove the amberlyst and theresultant filtrate was diluted with EtOAC and washed with water (10 mL)and brine (10 mL) then dried over Na₂SO₄, filtered and concentrated. Theresultant solid was recrystallized from MeOH to yield the product as awhite solid (0.05 g, 41%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.5-1.7 (m, 9H)2.20-2.22 (m, 2H), 2.49-2.90 (m, 10H), 3.39 (s, 3H), 3.78 (d, J=16 Hz,1H), 3.90 (d, J=16 Hz, 1H), 7.13 (s, 1H), 7.32 (s, 1H), 7.36 (d, J=8 Hz,1H), 7.61 (d, J=8 Hz, 1H), 10.9 (s, 1H). MS (ESI): 523 (M+H)⁺.

Example B(125)1-(2-Chloro-4-{2-[2-cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile

The title compound was prepared analogously to Example B(97) (where1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrilewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example and6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in thatexample. ¹H NMR (400 MHz, CDCl₃) δ: 1.38-1.42 (m, 2H), 1.47-1.73 (m,8H), 1.73-1.77 (m, 2H), 2.01-2.21 (m, 2H)), 2.39-2.50 (m, 1H), 2.56 (d,J=16 Hz, 1H), 2.63-2.69 (m, 2H), 2.80 (d, J=16 Hz, 1H), 3.3 (s, 3H),3.75 (d, J=16 Hz, 1H), 3.85 (d, J=16 Hz, 1H), 7.29 (dd, J=8, 1.6 Hz,1H), 7.43-7.45 (m, 2H), 8.74 (d, J=2.3 Hz, 1H), 9.01 (dd, J=2.3, 1,1 Hz,1H), 10.9 (s, 1H). C₂₉H₃₀ClN₅O₃.0.25: C, 64.68; H, 6.08; N, 13.00.Found: C, 64.78; H, 5.74; N, 12.65. MS (ESI): 532.2(M+H⁺).

Example B(126)1-(2-Chloro-4-{2-[5-(6-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile

The title compound was prepared analogously to Example B(97),1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrilewas substituted in place of6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dionein that example and6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in thatexample. ¹H NMR (400 MHz, CDCl₃) δ: 1.16-1.18 (m, 2H), 1.19-1.5 (m, 8H),1.51-1.53 (m, 2H), 1.86-1.89 (m, 2H)), 2.16-2.29 (m, 1H), 2.35-2.47 (m,3H), 2.59 (d, J=17 Hz, 1H), 3.56 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz,1H), 7.08 (d, J=7.8, 1 Hz, 1H), 7.20-7.23 (m, 2H), 8.70 (d, J=2.5 Hz,1H), 9.41 (d, J=2.5, 1,1 Hz, 1H), 10.7 (s, 1H). C₂₈H₂₇Cl₂N₅O₃.0.25: C,60.38; H, 4.98; N, 12.57. Found: C, 60.30; H, 4.80; N. 12.53.

MS (ESI): 552.2(M+H⁺).

Example C(1)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(quinolin-8-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), whereQuinoline-8-thiol was substituted in place of5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol.

¹H NMR (CDCl₃): δ 1.33 (d, J=6.1 Hz, 6H)1.39-1.74 (brm, 8H), 1.88 (m,2H), 2.36 (m, 1H), 2.53 (m, 2H), 2.74 (d, J=18 Hz 1H), 2.92 (m, 2H),4.42 (m, 1H), 6.81 (d, J=8.4 Hz 1H), 6.93 (d, J=7.8 Hz 1H), 7.01 (s,1H), 7.54-7.60 (m, 2H), 7.92 (d, J=8.1 Hz 1H), 8.33 (d, J=8.1 Hz 1H),8.51 (d, J=7.8 Hz 1H), 8.97 (s, 1H). Anal. Calcd. For C₃₀H₃₂FNO₄S: C,69.07; H, 6.18; N, 2.69. Found: C, 69.22; H, 6.08; N, 2.86.

Example C(2)3-(5-Chloro-1-isopropyl-1-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol was substituted in placeof 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol.

ESIMS (MH+): 588.3.

Example C(3)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(quinolin-8-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), whereQuinoline-8-thiol was substituted in place of5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol.

¹H NMR (CDCl₃): δ 1.25-1.74 (brm, 8H), 1.88 (m, 2H), 2.36 (m, 1H), 2.53(m, 2H), 2.74 (d, J=18 Hz 1H), 2.92 (m, 2H), 3.86 (s, 3H), 6.79 (d,J=8.4 Hz 1H), 6.91 (d, J=7.8 Hz 1H), 7.01 (s, 1H), 7.56-7.61 (m, 2H),7.90 (d, J=8.1 Hz 1H), 8.33 (d, J=8.1 Hz 1H), 8.47 (d, J=7.8 Hz 1H),8.97 (s, 1H). Anal. Calcd. For C₂₈H₂₈ClNO₄S: C, 65.94; H, 5.53; N, 2.75.Found: C, 65.68; H, 5.22; N, 2.85.

Example C(4):6-(2-Cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-3-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

A solution of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(150 mg, 0.46 mmol, from Step 1 below),5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (82 mg, 0.46 mmol), andtriethylamine (64 □L, 0.46 mmol) dissolved in DMF (5 mL) was heated to55° C. under N₂ for 8 h. The resulting mixture was concentrated andpurified by Prep HPLC to give the title compound (58 mg, 27%) as a paleyellow solid.

¹H NMR (DMSO-d₆): δ 1.62-1.82 (m, 12H), 2.03-2.11 (m, 8H), 2.51 (m, 1H),2.87 (d, 1H, J=17.5 Hz), 3.11 (d, 1H, J=17.5 Hz), 5.55 (s, 1H), 8.01 (d,2H, J=5.8 Hz), 8.84 (d, 2H, J=5.8 Hz). ESIMS: MH⁺467.15

Step 1:3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

Methyl-2-chloroacetoacetate (1.12 g, 7.42 mmol) was added to a cooled−40° C. suspension of NaH (0.3 g, 7.42 mmol, 60% dispersion in mineraloil) in THF (15 ml). After 20 min n-BuLi (3.0 mL, 7.42 mmol, 2.5M inhexanes) was added. The resulting dianion was stirred for an additional30 min and then treated with a solution of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one (0.51 g, 2.47 mmol,) in THF(10 ml). After stirring for 2 h at −40° C., the reaction mixture wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayers were washed with brine, dried with Na₂SO₄ and concentrated to ayellow oil that was used without further purification.

The oil was dissolved in toluene (8 mL), treated withbis(dibutylchlorotin)oxide (0.61 g, 1.1 mmol), and heated to 100° C.under N₂ for 1 h. The resulting mixture was concentrated and purified bysilica gel chromatography to give the title compound (0.31 g, 38%yield).

¹H NMR (CDCl₃): δ 1.41-1.72 (m, 12H), 1.75-2.0 (m, 8H), 2.31 (m, 1H),2.63 (d, 1H, J=17.8 Hz), 2.85 (d, 1H, J=17.8 Hz), 5.40 (s, 1H), 6.47 (brs, 1H). ESIMS: MH⁺325.20.

Example C(5)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(4), where5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol was substituted in placeof 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol.

¹HNMR(DMSO-d₆): δ 1.50-1.67 (m, 18H), 1.91-1.98 (m, 7H), 2.16 (m, 1H),2.37 (m, 1H), 2.59 (d, 1H, J=17.5 Hz), 2.92 (d, 1H, J=17.5 Hz), 4.14 (m,1H), 5.43 (s, 1H), 8.67 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.66 (d, 1H,J=8.7 Hz). Anal. Calcd. For C₂₈H₃₅N₂O₃SCl.0.3H₂O: C, 64.61; H, 6.89; N,5.38. Found: C, 64.57; H, 6.97; N, 5.18.

Example C(6):6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(5-hydroxy-4-isopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(40), where4-Isopropyl-5-mercapto-4H-[1,2,4]triazol-3-ol was substituted in placeof 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.50 (d, 6H, J=6.8 Hz) 1.42-1.67 (br m, 9H), 1.96(m, 2H), 2.40 (m, 1H), 2.51 (m, 1H), 2.73 (d, 1H, J=17.7 Hz), 2.90 (d,1H, J=17.7 Hz), 3.82 (s, 3H), 4.33 (m, 1H), 7.08 (m, 2H), 7.26 (s, 1H),11.60 (s, 1H), 12.31 (br s, 1H). Anal. Calcd. For C₂₄H₂₈N₃O₆ClS: C,55.22; H, 5.41, N, 8.05. Found: C, 55.02; H, 5.42, N, 8.17.

Example C(7)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(64), where5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was substituted inplace of 5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.26 (d, 6H, J=6.0 Hz), 1.44-1.73 (br m, 9H), 2.21(m, 2H), 2.39 (s, 3H), 2.53 (s, 3H), 2.58 (m, 2H), 2.71 (d, 1H, J=17.6Hz), 2.90 (d, 1H, J=17.6 Hz), 4.53 (s, 1H), 7.04-7.13 (m, 4H). Anal.Calcd. For C₂₈H₃₃N₄O₄FS.0.4 AcOH: C, 61.26; H, 6.18; N, 9.92. Found: C,61.33; H, 6.40, N, 9.70.

Example C(8)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(4-hydroxy-phenylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(64), where4-Mercapto-phenol was substituted in place of5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.34(d, 6H, J=6.0 Hz) 1.43-1.76 (br m, 8H), 1.97 (m,2H), 2.38 (m, 1H), 2.59 (m, 3H), 2.90 (d, 1H, J=17.9 Hz), 4.48 (m, 1H),6.70 (d, 2H, J=7.8 Hz), 6.80 (m, 3H), 7.25 (d, 2H, J=7.8 Hz). Anal.Calcd. For C₂₇H₃₁O₅FS.0.8H₂O: C, 64.73; H, 6.56. Found: C, 64.54; H,6.46.

Example C(9)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(64), where5-Methyl-[1,3,4]thiadiazole-2-thiol was substituted in place of5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.31 (d, 6H, J=5.8 Hz) 1.39-1.76 (br m, 9H), 2.05(m, 2H), 2.46 (m, 1H), 2.62 (m, 3H), 2.65 (m, 1H), 2.78 (d, 1H, J=17.9Hz), 3.00 (d, 1H, J=17.9 Hz), 4.59 (m, 1H), 6.99 (d, 1H, J=8.5 Hz), 7.10(s, 1H), 7.12 (d, 1H, J=8.5 Hz). Anal. Calcd. For C₂₄H₂₉N₂O₄FS₂.0.5H₂O:C, 57.46; H, 6.03; N, 5.58. Found: C, 57.43; H, 5.88; N, 5.54.

Example C(10)5-{6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-4H-[1,2,4]triazole-3-carboxylicAcid Methyl Ester

The title compound was prepared analogously to example C(64), where5-Mercapto-4-methyl-4H-[1,2,4]triazole-3-carboxylic acid methyl esterwas substituted in place of 5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.31 (d, 6H, J=6.0 Hz) 1.37-1.74 (br m, 9H), 2.05(m, 2H), 2.46 (m, 1H), 2.59 (m, 1H), 2.74 (d, 1H, J=17.6 Hz), 2.97 (d,1H, J=17.7 Hz), 3.85 (s, 3H), 3.94 (s, 3H), 4.58 (m, 1H), 6.99-7.15 (m,3H). Anal. Calcd. For C₂₆H₃₂N₃O₆FS-0.3H₂O: C, 57.93; H, 6.10; N, 7.80.Found: C, 57.89; H, 6.08; N, 7.64.

Example C(11)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(pyrimidin-2-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(64), wherePyrimidine-2-thiol was substituted in place of5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.27 (d, 6H, J=6.0 Hz) 1.37-1.74 (br m, 9H), 2.20(m, 2H), 2.60 (m, 2H), 2.73 (d, 1H, J=17.6 Hz), 2.94 (d, 1H, J=17.6 Hz),4.56 (m, 1H), 6.95 (d, 1H, J=8.3 Hz), 7.06 (m, 2H), 7.14 (t, 1H, J=4.7Hz), 8.40 (d, 2H, J=4.8 Hz). Anal. Calcd. For C₂₅H₂₉N₂O₄FS-0.3H₂O: C,62.82; H, 6.24; N, 5.86. Found: C, 62.76; H, 6.25; N, 5.75.

Example C(12)6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(5-hydroxy-4-isopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(64), where4-Isopropyl-5-mercapto-4H-[1,2,4]triazol-3-ol was substituted in placeof 5-chloro-1-methyl-1H-benzimidazole-2-thiol.

¹H NMR (DMSO-d₆): δ 1.27 (d, 6H, J=6.0 Hz), 1.39 (d, 6H, J=7.0 Hz),1.45-1.66 (br m, 9H), 1.96 (m, 2H), 2.4 (m, 1H), 2.54 (1H), 2.73 (d, 1H,J=17.8 Hz), 2.88 (d, 1H, J=17.7 Hz), 4.33 (m, 1H), 4.54 (m, 1H), 6.90(d, 1H, J=8.3 Hz), 7.02-7.11 (m, 2H). Anal. Calcd. ForC₂₆H₃₄N₃O₅FS-0.3H₂O: C, 59.48; H, 6.64; N, 8.00. Found: C, 59.58; H,6.64; N, 7.99.

Example C(13)6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared from3-Chloro-6-cyclopentyl-6{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-onefrom Step 2 and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiolusing the coupling method described in Example C(4),.

¹H NMR (DMSO-d₆): δ 1.44-1.75 (br m, 9H), 2.21 (s, 3H), 2.34 (s, 3H),2.38 (s, 3H), 2.59 (s, 3H), 2.65-2.79 (m, 3H), 2.97 (d, 1H, J=17.0 Hz),3.17 (s, 2H), 7.02 (s, 10H), 7.29 (d, 2H, J=8.1 Hz), 7.40 (d, 2H, J=8.1Hz). Anal. Calcd. For C₃₀H₃₃N₅O₄S.0.75 AcOH: C, 62.56; H, 6.00; N,11.58. Found: C, 62.66; H, 5.98; N, 11,56.

Step 1:1-Cyclopentyl-3-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-propan-1-one.

The title compound was prepared as described in Step 1 of Example A(82),where 4-(4-Bromo-phenyl)-3,5-dimethyl-isoxazole from Step 1 of ExampleA(18), was substituted for 2-Bromopyridine.

Step 2:3-Chloro-6-cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared as described in Step 1 of Example C(4),where1-Cyclopentyl-3-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-propan-1-one wassubstituted for 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one).

Example C(14)3-(5-Chloro-1-methyl-1H-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to example C(13) where5-Chloro-1-methyl-1H-benzoimidazole-2-thiol was substituted in place of5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol.

¹H NMR (CDCl₃): δ 1.27-1.74 (br m, 9H), 2.09 (m, 2H), 2.25 (s, 3H), 2.38(s, 3H), 2.39 (m, 1H), 2.70 (m, 3H), 3.93 (s, 3H), 7.14 (d, 2H, J=8.1Hz), 7.21 (d, 2H, J=8.1 Hz), 7.26-7.34 (m, 2H), 7.55 (s, 1H). Anal.Calcd. For C₃₁H₃₂N₃O₄SCl.0.7H₂O: C, 63.03; H, 5.70; N, 7.11. Found: C,63.01; H, 5.75; N, 6.97.

Example C(15)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared from3-Chloro-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-onefrom Step 1 and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using thecoupling method described in Example C(4),

¹H NMR (CDCl₃): δ 0.96 (t, 3H, J=7.5 Hz), 1.69 (d, 6H, J=7.0 Hz), 1.85(m, 2H), 1.98 (m, 2H), 2.59 (m, 2H), 2.71 (s, 2H), 3.78 (s, 3H), 5.16(m, 1H), 6.81 (d, 2H, J=8.5 Hz), 7.06 (d, 2H, J=8.5 Hz), 7.28 (d, 2H,J=8.9 Hz), 7.48 (d, 1H, J=8.9 Hz), 7.59 (s, 1H). ESIMS: MH⁺501.10,503.10, MH⁻4.99.10, 501.10.

Step 1:3-Chloro-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared as described in Step 1 of Example C(4),where 1-(4-Methoxy-phenyl)-pentan-3-one (from Step 2 of Example A(23))was substituted in place of cyclohex-1-enyl-1-cyclopentyl-propan-1-one.

Example C(16):3-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(15) where5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was substituted inplace of 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol.

¹H NMR (CDCl₃): δ 1.01 (t, 3H, J=7.4 Hz), 1.97 (m, 2H), 2.10 (m, 2H),2.62 (s, 3H), 2.63 (s, 3H), 2.68 (m, 2H), 2.83 (s, 2H), 3.78 (s, 3H),6.76 (s, 1H), 6.82 (d, 2H, J=8.5 Hz), 7.12 (d, 2H, J=8.5 Hz). Anal.Calcd. For C₂₃H₂₆N₄O₄S-0.6H₂O: C, 59.36; H, 5.89; N, 12.04. Found: C,59.26; H, 5.76; N, 11.52.

Example C(17)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-apyrimidin-2-ylsulfanyl)-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one

The title compound was prepared from3-Chloro-6-cyclopentyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one(described in Step 2 below) and5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the couplingmethod described in Example C(4). ¹H NMR (CDCl₃): δ 1.54 (s, 3H),1.55-2.32 (br m, 9H), 2.59 (m 1H), 2.64 (s, 3H), 2.71 (s, 3H), 2.96 (m,1H), 6.77 (s, 1H). ESIMS: MH⁺375.10, MH⁻373.10.

Step 1: 1-Cyclopentyl-ethanone

Cyclopentylmagnesium bromide (5 mL, 10 mmol, 2M soln in THF) was addedto a cooled −78° C. solution of acetic anhydride (0.8 mL, 8.33 mmol)dissolved in THF (20 mL). The reaction mixture was stirred for 60 min.The reaction was quenched with saturated NH₄Cl and extracted with EtOAc.The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a yellow oil. The residue was purified by silica gelchromatography (hexanes) to give the title compound as an oil (0.5 g,54%).

¹H NMR (CDCl₃): δ 1.55-1.84 (br m, 8H), 2.16 (s, 3H), 2.87 (m, 1H).

Step 2:3-Chloro-6-cyclopentyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in Step 1 of Example C(4),where 1-Cyclopentyl-ethanone (from Step 1) was substituted in place ofcyclohex-1-enyl-1-cyclopentyl-propan-1-one.

ESIMS: MH⁺231.10, MH⁻230.10.

Example C(18)3-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared from3-Chloro-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one (from Step 1) and5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the couplingmethod described in Example C(4). ¹H NMR (CDCl₃): δ 0.97 (t, 6H, J=7.5Hz), 1.85 (m, 2H), 1.94 (m, 2H), 2.63 (s, 3H), 2.71 (s, 3H), 2.78 (s,2H), 6.78 (s, 1H). Anal. Calcd. For C₁₆H₂₀N₄O₃S-0.5H₂O: C, 53.76; H,5.92; N, 15.68. Found: C, 53.96; H, 5.84; N, 15.37.

Step 1: 3-Chloro-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared as described in Step 1 of Example C(4),where 3-pentanone was substituted in place ofcyclohex-1-enyl-1-cyclopentyl-propan-1-one.

Example C(19)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(18) where5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol was substituted in placeof 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol. ¹H NMR(CDCl₃): δ 0.91 (t, 6H, J=7.4 Hz), 1.68 (d, 6H, J=7.0 Hz), 1.69-1.85 (m,4H), 2.64 (s, 2H), 5.16 (m, 1H), 6.34 (br s, 1H), 7.28 (d, 1H, J=8.9Hz), 7.48 (d, 1H, J=8.9 Hz), 7.59 (s, 1H). Anal. Calcd. ForC₁₉H₂₃N₂O₃SCl.0.2H₂O: C, 57.26; H, 5.92; N, 7.03. Found: C, 57.31; H,5.89; N, 7.02.

Example C(20)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one

The title compound was prepared from3-Chloro-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (fromStep 1) and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using thecoupling method described in Example C(4).

¹H NMR (CDCl₃): δ 0.95 (t, 3H, J=7.5 Hz), 1.41 (s, 3H), 1.68 (d, 6H,J=7.0 Hz), 1.75 (m, 2H), 2.52 (d, 1H, J=17.1 Hz), 2.74 (d, 1H, J=17.1Hz), 6.97 (m, 1H), 6.56 (br s, 1H), 7.28 (d, 1H, J=8.9 Hz), 7.48 (d, 1H,J=8.9 Hz), 7.60 (s, 1H). Anal. Calcd. For C₁₈H₂₁N₂O₃SCl.0.1H₂O: C,56.49; H, 5.58; N, 7.32. Found: C, 56.32; H, 5.56; N, 7.17.

Step 1: 3-Chloro-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

The title compound was prepared as described in Step 1 of Example C(4),where 2-butanone was substituted in place ofcyclohex-1-enyl-1-cyclopentyl-propan-1-one.

Example C(21)3-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-6-ethyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(20) where5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was substituted inplace of 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol.

¹H NMR (CDCl₃): δ 1.01 (t, 3H, J=7.4 Hz), 1.54 (s, 3H), 1.87 (m, 2H),2.63 (s, 3H), 2.68 (d, 1H, J=17.5 Hz), 2.71 (s, 3H), 2.90 (d, 1H, J=17.5Hz), 6.78 (m, 1H). Anal. Calcd. For C₁₅H₁₈N₄O₃S.0.4AcOH: C, 52.94; H,5.51; N, 15.63. Found: C, 52.63; H, 5.43; N, 15.92.

Example C(22)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example C(4), where3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneStep 1 of example C(40), was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Phenyl-1H-1,2,4-triazole-3-thiol was substituted in place of5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 1.53-1.85 (m, 10H), 2.17-2.34 (m, 1H), 2.69-2.75 (m2H), 2.95 (d, J=17.0, 1H), 3.08 (d, J=17.0 Hz, 1H), 3.90 (s, 3H), 7.08(d, J=8.4 Hz, 1H) 7.22-7.26 (m, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.40-7.53(m, 4H), 7.91-7.94 (m, 2H), 12.0 (brs, 1H); Anal. Calcd. ForC₂₇H₂₈ClN₃O₄S.1.0 HCl.1.0H₂O: C, 55.86; H, 5.38, N, 7.24; Found: C,55.75; H, 5.17, N, 7.17. ESIMS (MH+): 527.

Example C(23)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-[5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example C(4), where3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneexample C(40), was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 4H-3-mercapto-5-(4-hydroxyphenyl)[1,2,4]-triazole was substituted inplace of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 1.47-1.76 (m, 10H), 2.04-2.23 (m, 1H), 2.58-2.64 (m2H), 2.83 (d, J=17.0, 1H), 2.94 (d, J=17.0 Hz, 1H), 3.81 (s, 3H), 6.76(d, J=8.7 Hz, 1H) 6.98 (d, J=8.5 Hz, 2H), 7.13 (dd, J=8.5, 2.0 Hz, 1H),7.29 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 9.88 (s, 1H), 12.0 (brs,1H); Anal. Calcd. For C₂₇H₂₈ClN₃O₅S.1.0 HCl 1.0H₂O: C, 54.36; H, 5.24,N, 7.04; Found: C, 54.38; H, 5.02, N, 7.24.

ESIMS (MH+): 543.

Example C(24):6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-3-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-onefrom Step 1 of example C(64), was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one,and 5-Phenyl-1H-1,2,4-triazole-3-thiol was substituted in place of5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 1.24 (d, J=6.0 Hz, 6H), 1.39-1.73 (m, 10H),1.97-2.00 (m, 1H), 2.58-2.62 (m 2H), 2.81 (d, J=17.0, 1H), 2.96 (d,J=17.0 Hz, 1H), 4.46-4.54 (m, 1H), 6.91-7.09 (m, 3H), 7.38-7.41 (m, 3H),7.82-7.84 (m, 2H), 14.2 (brs, 1H); Anal. Calcd. For C₂₉H₃₂FN₃O₄S: C,64.79; H, 6.0, N, 7.82; Found: C, 64.52; H, 6.16, N, 7.75. ESIMS (MH+):538.

Example C(25)6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-3-(5-chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-yclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(from Step 1 below) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted inplace of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 1.13 (d, J=6.1 Hz, 6H), 1.41 (d, J=7.1 Hz, 6H),1.42-1.8 (m, 10H), 2.08-2.13 (m, 1H), 2.43-2.54 (m 3H), 2.79 (d, J=17.0,1H), 4.44-4.48 (m, 1H), 4.63-4.69 (m, 1H), 6.89-6.91 (m, 2H), 6.95-7.00(m, 2H), 7.14 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 12.0 (brs, 1H); Anal.Calcd. For C₃₁H₃₆Cl₂N₂O₄S.1.0 AcOH: C, 59.72; H, 6.07, N, 4.22; Found:C, 59.50; H, 6.16, N, 4.33. ESIMS (MH+): 604.

Step 1: 3-Chloro-6-[2-(3-chloro4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The pyrone intermediate, was prepared analogously to Example C(4), where3-(3-Chloro-4-isopropoxy-phenyl)-1-cyclopentyl-propan-1-one (from Step 2below) was substituted in place of3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one in Step 1 of that example.

Step 2: 3-(3-Chloro-4-isopropoxy-phenyl)-1-cyclopentyl-propan-1-one

The ketone intermediate, was prepared analogously to Example A(27),where 4-Bromo-2-chloro-1-isopropoxy-benzene (from Step 3 below) wassubstituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one inStep 1 of that example.

Step 3: 4-Bromo-2-chloro-1-isopropoxy-benzene

The intermediate bromide, was prepared analogously to Step 1 in ExampleA(52), where 4-Bromo-2-chloro-phenol was substituted in place of4-bromo-2-fluorophenol and 2-iodopropane instead of methyl□-bromobutyrate of that example.

Example C(26)3-(5-Chloro-1H-benzoimidazol-2-ylsulfanyl)-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-onewas substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Chloro-benzimidazole-2-thiol was substituted in place of5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 1.34 (d, J=6.1 Hz, 6H), 1.41-1.82 (m, 10H),2.07-2.14 (m, 1H), 2.55-2.88 (m, 4H), 3.4 (brs, 1H), 4.44-4.48 (m, 1H),6.81-6.91 (m, 2H), 7.13-7.39 (m, 4H), 12.0 (brs, 1H); ESIMS (MH+)(C₂₈H₃₀Cl₂N₂O₄S): 562.

Example C(27)6-(2-Cyclohexyl-ethyl)-6-cyclopentyl-4-hydroxy-3-(5-pyridin-4-yl-4H-1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Cyclohexyl-1-cyclopentyl-propan-1-one from Step 2 of Example A(44),was substituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-onein Step 1 of that example.

¹H NMR (CDCl₃): δ 0.5-3.4 (m, 28H), 7.84 (d, J=6.0, 2H), 8.66 (d, J=6.0,2H); Anal. Calcd. For C₂₅H₃₂N₄O₃S: C, 64.08; H, 6.88, N, 11.96; Found:C, 64.30; H, 6.68, N=11.90. ESIMS (MH+): 345.

Example C(28)6-Cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-3-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-one(from Step 2 below) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneof that example.

¹H NMR (DMSO-d₆): 60.96-1.86 (m, 21H), 2.24-2.26 (m, 1H), 2.61 (d,J=17.0, 1H), 2.90 (d, J=17.0, 1H), 3.31 (brs, 1H), 7.80-7.88 (m, 2H),8.61-8.71 (m, 2H), 14.0 (brs, 1H); Anal. Calcd. For C₂₄H₃₀N₄O₃S: C,63.41; H, 6.65, N, 12.32; Found: C, 63.20; H, 6.90, N, 12.60. ESIMS(MH+): 454.

Step: 1: 4-Cyclopentyl-1-cyclopentyl-butan-1-one

The title compound was prepared analogously to Example A(44), where3-cyclopentyl propionic acid was substituted in place of3-cyclohexylpropionic acid in Step 1 of that example.

¹H NMR (DMSO-d₆): 60.79-0.91 (m, 2H), 1.11-1.24 (m, 5H), 1.55-1.88 (m,12H), 2.41 (t, J=7.4, 2H), 2.81-2.91 (m, 1H).

Step 2:2-Chloro-5-cyclopentyl-5-(2-cyclopentyl-ethyl)-3-hydroxy-cyclohex-2-enone

The title compound was prepared analogously to Example C(4), where4-Cyclopentyl-1-cyclopentyl-butan-1-one from Step 1 above wassubstituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one ofthat example.

¹H NMR (CDCl₃): δ 0.86-1.73 (m, 23H), 2.24-2.31 (m, 1H), 2.62 (d, J=17,1H), 2.83 (d, J=17, 1H).

ESIMS (MH+): 311.

Example C(29)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-4-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-onefrom Step 2 of example C(28) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted inplace of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 0.84-2.28 (m, 28H), 2.31 (d, J=17.0, 1H), 2.66 (d,J=17.0, 1H), 3.96 (brs, 1H), 4.55-4.67 (m, 1H), 6.93 (d, J=8.5, 1H),7.12 (s, 1H), 7.46 (d, J=8.5, 1H); Anal. Calcd. For C₂₇H₃₅ClN₂O₃S: C,64.46; H, 7.01, N, 5.57; Found: C, 64.85; H, 7.30, N, 5.76. ESIMS (MH+):504.

Example C(30)6-(3-Cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-3-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(described in Step 2 below) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneof that example.

¹HNMR(DMSO-d₆): δ 0.5-1.86 (m, 25H), 2.08-2.10 (m, 1H), 2.42 (d, J=17.0,1H), 2.71 (d, J=17.0, 1H), 3.11 (brs, 1H), 7.61 (d, J=5.8, 2H), 8.43 (d,J=4.5, 2H), 11.71 (brs, 1H); Anal. Calcd. For C₂₆H₃₄N₄O₃S-0.5AcOH-0.75H₂O: C, 61.63; H, 7.18, N, 10.65; Found: C, 61.55; H, 7.06, N,10.98. ESIMS (MH+): 483.

Step 1: 4-Cyclohexyl-1-cyclopentyl-butan-1-one

The title compound was prepared analogously to Example A(44), wherecyclohexanebutyric acid was substituted in place of3-cyclohexylpropionic acid in Step 1 of that example.

¹H NMR (DMSO-d₆): δ 0.79-0.91 (m, 2H), 1.11-1.27 (m, 7H), 1.55-1.85 (m,14H), 2.41 (t, J=7.4, 2H), 2.81-2.91 (m, 1H).

Step 2:3-Chloro-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-on

The title compound was prepared analogously to Example C(4), where4-Cyclohexyl-1-cyclopentyl-butan-1-one from Step 1 above was substitutedin place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one of thatexample.

¹H NMR (CDCl₃): δ 0.86-1.75 (m, 26H), 2.27-2.32 (m, 1H), 2.61 (d, J=17,1H), 2.83 (d, J=17, 1H).

ESIMS (MH+): 341.

Example C(31)3-(5-Chloro-1-isopropyl-1H-benzoimidazol-2-ylsulfanyl)-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(described in Step 2 of example C(30) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted inplace of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 0.63-1.39 (m, 23H), 1.38 (d, J=6.9, 6H), 1.70-1.73(m, 2H), 2.14-2.20 (m, 1H), 2.39 (d, J=17.0, 1H), 2.71 (d, J=17.0, 1H),4.58-4.67 (m, 1H), 6.96 (dd, J=8.6, 2.1, 1H), 7.17 (d, J=2.1, 1H), 7.49(d, J=8.6, 1H) 12.9 (brs, 1H); Anal. Calcd. For C₂₉H₃₉ClN₂O₃S-0.5H₂O: C,64.48; H, 7.46, N, 5.19; Found: C, 64.69; H, 7.30, N, 5.15. ESIMS (MH+):532.

Example C(32)6-(4-Cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-3-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-(4-cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(from Step 2 below) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneof that example.

¹H NMR (DMSO-d₆): δ 0.87-1.75 (m, 27H), 2.13-2.16 (m, 1H), 2.49 (d,J=17.0, 1H), 2.78 (d, J=17.0, 1H), 3.27 (brs, 1H), 7.70 (d, J=6.0, 2H),8.50 (d, J=5.3, 2H), 13.9 (brs, 1H); Anal. Calcd. ForC₂₇H₃₆N₄O₃S.1.5H₂O: C, 61.93; H, 7.51, N, 10.70; Found: C, 62.22; H,7.30, N, 10.87. ESIMS (MH+): 497.

Step 1: 5-Cyclohexyl-1-cyclopentyl-pentan-1-one

The title compound was prepared analogously to Example A(44), wherecyclohexanepentanoic acid was substituted in place of3-cyclohexylpropionic acid in Step 1 of that example.

¹H NMR (DMSO-d₆): δ 0.79-0.91 (m, 2H), 1.11-1.85 (m, 23H), 2.40 (t,J=7., 2H), 2.8-2.90 (m, 1H).

Step 2:3-Chloro-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where5-Cyclohexyl-1-cyclopentyl-pentan-1-one from Step 1 above wassubstituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one ofthat example.

¹H NMR (CDCl₃): δ 0.86-1.80 (m, 28H), 2.25-2.31 (m, 1H), 2.6 (d, J=17,1H), 2.85 (d, J=17, 1H).

ESIMS (MH+): 355.

Example C(33):6-(4-Cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-3-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example C(4), where3-Chloro-6-(4-cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one(described in Step 2 of example C(32) was substituted in place of3-Chloro-6-(2-cyclohex-1-enyl-ethyl)₆-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-oneand 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted inplace of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.

¹H NMR (DMSO-d₆): δ 0.73-1.36 (m, 23H), 1.43 (d, J=7.4, 6H), 1.49-1.55(m, 2H), 1.84-1.88 (m, 2H), 2.18-2.23 (m 1H), 2.41 (d, J=17.0, 1H), 2.77(d, J=17.0, 1H), 4.65-4.74 (m, 1H), 7.02 (dd, J=8.6, 1.9, 1H), 7.22 (d,J=1.9, 1H), 7.54 (d, J=8.6, 1H), 12.9 (brs, 1H); Anal. Calcd. ForC₃₀H₄₁ClN₂O₃S.1.25H₂O: C, 63.47; H, 7.72, N, 4.93; Found: C, 63.27; H,7.44, N, 4.80. ESIMS (MH+): 546.

Example C(34)3-[(4-tert-butyl-4H-1,2,4-triazol-3-yl)thio]-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), , where4-tert-butyl-4H-1,2,4-triazole-3-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58 (m, 1H), 1.79 (m, 6H), 1.89 (s,9H), 1.90 (m, 2H), 2.24 (m, 1H), 2.38 (m, 1H), 2.68 (m, 1H), 2.80 (m,2H), 2.84 (d, J=17.3 Hz, 1H), 3.13 (d, J=17.3 Hz, 1H), 4.05 (s, 3H),7.26 (d, J=8.4 Hz, 1H), 7.51 (dd, J=8.4, 2.1 Hz, 1H), 7.58 (d, J=2.1 Hz,1H), 8.82 (s, 1H). Anal. Calcd. For C₂₅H₃₂ClN₃O₄S: C, 59.33; H, 6.37; N,8.30; S, 6.34. Found: C, 59.07; H, 6.46; N, 8.13; S, 6.18.

Example C(35)6-[2-(3-chloro-4-methoxyphenyl)ethyl]”-cyclopentyl-3-[(4-ethyl-4H-1,2,4-triazol-3-yl)thio]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), , where4-ethyl-4H-1,2,4-triazole-3-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.24 (m, 1H), 1.26 (t, J=7.3 Hz, 3H),1.49 (m, 7H), 1.90 (m, 2H), 2.29 (m, 1H), 2.43 (m, 2H), 2.56 (d, J=17.5Hz, 1H), 2.80 (d, J=17.5 Hz, 1H), 3.73 (s, 3H), 3.97 (q, J=7.3 Hz, 2H),6.94 (d, J=8.5 Hz, 1H), 7.11 (dd, J=8.5, 2.1 Hz, 1H), 7.21 (d, J=2.1 Hz,1H), 8.54 (s, 1H). Anal. Calcd. For C₂₃H₂₈ClN₃O₄S: C, 57.79; H, 5.90; N,8.79; S, 6.71. Found: C, 57.62; H, 5.93; N, 8.69; S, 6.65.

Example C(36)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-isopropyl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where4-isopropyl-4H-1,2,4-triazole-3-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.43 (d, J=6.6 Hz, 3H), 1.44 (d, J=6.6Hz, 3H), 1.48 (m, 8H), 1.99 (m, 2H), 2.39 (m, 1H), 2.53 (m, 2H), 2.65(d, J=17.5 Hz, 1H), 2.89 (d, J=17.5 Hz, 1H), 3.82 (s, 3H), 4.59 (dq,J=6.6, 6.6 Hz, 1H), 6.51 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.20 (dd,J=8.4, 2.2 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 8.76 (s, 1H). Anal. Calcd.For C₂₄H₃₀ClN₃O₄S: C, 58.59; H, 6.15; N, 8.54; S, 6.52. Found: C, 58.35;H, 6.29; N, 8.29; S, 6.27.

Example C(37)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-phenyl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), , where4-phenyl-4H-1,2,4-triazole-3-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, CDCL₃) δ ppm 1.37 (m, 1H), 1.63 (m, 8H), 2.00 (m, 2H),2.35 (m, 1H), 2.60 (m, 2H), 2.91 (d, J=17.8 Hz, 1H), 3.10 (d, J=17.8 Hz,1H), 3.85 (s, 3H), 6.82 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 2.1 Hz, 1H),7.15 (d, J=2.1 Hz, 1H), 7.60 (m, 5H), 8.27 (s, 1H). Anal. Calcd. ForC₂₇H₂₈ClN₃O₄S: C, 61.65; H, 5.36; N, 7.99; S, 6.10. Found: C, 61.53; H,5.41; N, 7.74; S, 5.92.

Example C(38)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-methyl-1H-tetrazol-5-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), , where1-methyl-1H-tetrazole-5-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, CDCL₃) δ ppm 1.36 (s, 1H), 1.59 (m, 8H), 2.00 (dd,J=11.0, 5.4 Hz, 2H), 2.35 (s, 1H), 2.59 (dd, J=11.0, 6.0 Hz, 2H), 2.90(d, J=17.9 Hz, 1H), 3.09 (d, J=17.9 Hz, 1H), 3.87 (s, 3H), 4.25 (s, 3H),6.83 (d, J=8.5 Hz, 1H), 6.98 (dd, J=8.5, 2.1 Hz, 1H), 7.14 (d, J=2.1 Hz,1H). Anal. Calcd. For C₂₁H₂₅ClN₄O₄S.0.1H₂O: C, 54.03; H, 5.44; N, 12.00;S, 6.87. Found: C, 53.90; H, 5.45; N, 11.74; S, 6.75.

Example C(39)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-ethyl-1H-tetrazol-5-yl)thio]4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), , where1-ethyl-1H-tetrazole-5-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (400 MHz, CDCL₃) δ ppm 1.34 (m, 1H), 1.59 (m, 8H), 1.63 (t, J=7.3Hz, 3H), 1.99 (m, 2H), 2.36 (m, 1H), 2.59 (m, 2H), 2.90 (d, J=17.9 Hz,1H), 3.10 (d, J=17.9 Hz, 1H), 3.87 (s, 3H), 4.65 (q, J=7.3 Hz, 2H), 6.83(d, J=8.3 Hz, 1H), 6.99 (dd, J=8.3, 2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H).Anal. Calcd. For C₂₂H₂₇ClN₄O₄S: C, 55.16; H, 5.68; N, 11.70; S, 6.69.Found: C, 55.22; H, 5.64; N, 11.48; S, 6.54.

Step 1:2-Chloro-7-(3-chloro-4-methoxy-phenyl)-5-cyclopentyl-5-hydroxy-3-oxo-heptanicAcid Methyl Ester

Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0°C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil)in THF (30 ml). After 15 min the solution was cooled to −40° C. andn-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resultingdianion was stirred for an additional 30 min and then treated with asolution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one(1.5 g, 5.6 mmol, compound was prepared analogously to Step 1 of ExampleA(82), where 4-bromo-2-chloro-1-methoxybenzene was substituted in placeof 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C.,the reaction mixture was quenched with saturated NH₄Cl and extractedwith EtOAc. The organic layers were washed with brine, dried with Na₂SO₄and concentrated to an orange oil that was used without furtherpurification.

Step 2:3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

A solution of2-Chloro-7-(3-chloro-4-methoxy-phenyl)-5-cyclopentyl-5-hydroxy-3-oxo-heptanoicacid methyl ester (2.33 g, 5.6 mmol, from Step 1), andbis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol), dissolved in toluene (18mL) were heated at reflux for 30 mins. The resulting mixture wasconcentrated and purified by silica gel chromatography to give the titlecompound (1.57 g, 75% yield, two Steps).

¹H NMR (CDCl₃): δ 1.36-1.79 (br m, 8H), 2.02 (m, 2H), 2.41 (m, 1H), 2.65(m, 3H), 2.89 (d, 1H, J=17.7 Hz), 3.88 (s, 3H), 6.47 (br s, 1H), 6.85(d, 1H, J=8.4 Hz), 7.01 (dd, 1H, J=8.4, 2.1 Hz), 7.16 (d, 1H, J=2.1 Hz).

Example C(40)3-[(5-chloro-1-isopropyl-1H-benzimidazol-2-yl)thio]-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

A solution of3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one(300 mg, 0.78 mmol), 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol (181mg, 0.80 mmol) and Et₃N (0.1 mL, 0.80 mmol) was stirred at 55° C. for 5hrs. The mixture was concentrated and purified by prep HPLC to obtain 50mg product (11% yield).

¹H NMR (300 MHz, DMSO-D₆)δ: 1.49-1.61 (m, 14H) 2.23-2.30 (m, 2H)2.57-2.66 (m, 4H) 2.91-2.96 (m, 1H), 3.81 (s, 3H) 4.73-4.79 (m, 1H) 6.93(d, J=2.07 Hz, 1H), 7.03 (d, J=8.48 Hz, 1H), 7.09 (dd, J=8.57, 2.17 Hz,1H), 7.12-7.16 (m, 1H), 7.28 (d, J=1.88 Hz, 1H), 7.62 (d, J=8.67 Hz,1H). ESI-MS calcd for C₂₉H₃₂Cl₂N₂O₄S: 574.1. Found (M+H⁺): 575.0. Anal.Calcd for C₂₉H₃₂Cl₂N₂O₄S: C, 60.52; H, 5.60; N, 4.87. Found: C, 60.51;H, 5.74; N, 4.58.

Example C(41)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[1(1-methyl-1H-benzimidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1-methyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.51-1.70 (m, 8H), 2.02-2.08 (m, 2H),2.35-2.43 (m, 1H), 2.55-2.60 (m, 3H), 2.75-2.80 (m, 1H), 3.81 (s, 6H),7.02 (d, J=8.48 Hz, 1H), 7.10-7.13 (m, 1H), 7.25-7.34 (m, 4H), 7.39 (d,J=8.10 Hz, 1H), 7.62 (d, J=7.35 Hz, 1H). ESI-MS calcd for C₂₇H₂₉ClN₂O₄S:512.2. Found (M+H⁺): 513.0. Anal. Calcd for C₂₇H₂₉ClN₂O₄S.0.6H₂O: C,61.68; H, 5.76; N, 5.10; S, 5.84. Found: C, 61.71; H, 5.75; N, 5.16; S,5.85.

Example C(42)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-{[5-(2-furyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-(2-furyl)-4-methyl-4H-1,2,4-triazole-3-thiol was substituted in placeof 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.17-1.45 (m, 8H) 1.67-1.74 (m, 2H),2.08-2.16 (m, 2H), 2.29-2.32 (m, 1H), 2.39-2.45 (m, 1H), 2.61-2.67 (m,1H), 3.54 (s, 3H), 3.56 (s, 3H), 6.49 (dd, J=3.39, 1.88 Hz, 1H), 6.75(d, J=8.48 Hz, 1H), 6.83 (d, J=3.39 Hz, 1H), 6.89 (dd, J=8.48, 2.07 Hz,1H), 7.05 (d, J=2.07 Hz, 1H), 7.70-7.72 (m, 1H). ESI-MS calcd forC₂₆H₂₈ClN₃O₅S: 529.1. Found (M+H⁺): 530.0. Anal. Calcd forC₂₆H₂₈ClN₃O₅S.0.2 HOAc: C, 58.50; H, 5.36; N, 7.75; S, 5.92. Found: C,58.34; H, 5.32; N, 7.81; S, 5.92.

Example C(43)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(1H-imidazo[4,5-b]pyridin-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1H-imidazo[4,5-b]pyridine-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.38-1.75 (m, 8H), 2.05-2.11 (m, 2H),2.40-2.45 (m, 1H), 2.57-2.63 (m, 2H), 2.69-2.75 (m, 1H), 2.93-2.99 (m,1H), 3.81 (s, 3H), 7.05 (d, J=8.48 Hz, 1H), 7.13 (dd, J=7.91, 4.90 Hz,1H), 71.8-7.22 (m, 1H), 7.31 (d, J=2.07 Hz, 1H), 7.67 (dd, J=7.82, 1.22Hz, 1H), 8.19 (dd, J=4.90, 1.32 Hz, 1H). ESI-MS calcd for C₂₅H₂₆ClN₃O₄S:499.1. Found (M+H⁺): 500.00. Anal. Calcd. For C₂₅H₂₆ClN₃O₄S. 1.0 HOAc:C, 57.90; H, 5.40; N, 7.50; S, 5.73. Found, C, 57.99; H, 5.37; N, 7.29;S, 6.04.

Example C(44)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-isopropyl-1H-benzimidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1-isopropyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.45-1.70 (m, 14H), 2.04-2.10 (m, 2H),2.37-2.43 (m, 1H), 2.55-2.60 (m, 2H), 2.71-2.76 (m, 1H), 3.81 (s, 3H),4.89-4.92 (m, 1H), 7.02 (d, J=8.48 Hz, 1H), 7.11-7.14 (m, 1H), 7.19-7.22(m, 2H), 7.25 (d, J=1.88 Hz, 1H), 7.29-7.32 (m, 1H), 7.71-7.74 (m, 1H).ESI-MS calcd for C₂₉H₃₃ClN₂O₄S: 540.2. Found (M+H⁺) 541.1. Anal. Calcd.For C₂₉H₃₃ClN₂O₄S. 1.5HOAc: C, 60.89; H, 6.23; N, 4.44. Found: C, 61.02;H, 6.34; N, 4.82.

Example C(45):3-(1,3-benzothiazol-2-ylthio)-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1,3-benzothiazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.39-1.73 (m, 8H), 2.11-2.16 (m, 2H),2.43-2.45 (m, 1H), 2.62-2.67 (m, 2H), 2.80-2.86 (m, 1H), 2.99-3.05 (m,1H), 3.83 (s, 3H), 7.07 (d, J=8.48 Hz, 1H), 7.16-7.19 (m, 1 H),7.28-7.34 (m, 2H), 7.37-7.43 (m, 1H), 7.66 (d, J=7.54 Hz, 1H), 7.79-7.82(m, 1H). ESI-MS calcd for C₂₆H₂₆ClNO₄S₂: 515.1. Found (M+H⁺): 516.2.Anal. Calcd for C₂₆H₂₆ClNO₄S₂: C, 60.51; H, 5.08; N, 2.71. Found: C,60.30; H, 5.24; N, 2.71.

Example C(46):6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(1H-imidazo[4,5-c]pyridin-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1H-imidazo[4,5-c]pyridine-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.45-1.68 (m, 8H), 1.93-1.99 (m, 2H),2.35-2.40 (m, 2H), 2.54-2.60 (m, 2H), 2.70-2.72 (m, 1H), 3.80 (s, 3H),7.03 (d, J=8.48 Hz, 1H), 7.10-7.12 (m, 1H), 7.22 (d, J=2.07 Hz, 1H),7.70 (d, J=6.41 Hz, 1H), 8.34 (d, J=6.40 Hz, 1H), 8.83 (s, 1H). ESI-MScalcd for C₂₅H₂₆ClN₃O₄S: 499.1. Found (M+H⁺): 500.0. Anal. Calcd. ForC₂₅H₂₆ClN₃O₄S.0.9H₂O: C, 58.16; H, 5.43; N, 8.14; S, 6.21. Found: C,58.29; H, 5.41; N, 8.10; S, 5.94.

Example C(47)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where[1,3]thiazolo[5,4-b]pyridine-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.37-1.76 (m, 8H), 2.04-2.14 (m, 2H),2.60-2.65 (m, 2H), 2.81-3.02 (m, 3H), 3.82 (s, 3H), 7.05 (d, J=8.48 Hz,1H), 7.16 (m, 1H), 7.30 (d, J=1.88 Hz, 1H), 7.45 (dd, J=8.29, 4.71 Hz,1H), 8.00 (dd, J=8.29, 1.51 Hz, 1H), 8.43 (dd, J=4.62, 1.41 Hz, 1H).ESI-MS calcd for C₂₅H₂₅ClN₂O₄S₂: 516.1. Found (M+H⁺): 517.0. Anal. Calcdfor C₂₅H₂₅ClN₂O₄S₂: C, 58.07; H, 4.87; N, 5.42; S, 12.40. Found: C,57.71; H, 4.87; N, 5.40; S, 12.13.

Example C(48)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-phenyl-1H-benzimidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where1-phenyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.41-1.73 (m, 8H), 2.20-2.29 (m, 2H),2.60-2.74 (m, 3H), 2.89-2.93 (m, 2H), 3.83 (s, 3H), 7.06 (d, J=8.59 Hz,1H), 7.13-7.21 (m, 6H), 7.32 (d, J=2.02 Hz, 1H), 7.59-7.60 (m, 2H),7.63-7.68 (m, 2H). ESI-MS calcd for C₃₂H₃₁ClN₂O₄S: 574.2. Found (M+H⁺):575.2. Anal. Calcd. For C₃₂H₃₁ClN₂O₄S.0.2H₂O: C, 66.41; H, 5.47; N,4.84; S, 5.54. Found: C, 66.34; H, 5.43; N, 4.93; S, 5.44.

Example C(49)3-[(5-chloro-1H-benzimidazol-2-yl)thio]-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-chloro-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) 8:1.36-1.71 (s, 8H), 2.05-2.13 (m, 2H),2.38-2.43 (m, 1H), 2.56-2.72 (m, 3H), 2.86-2.93 (m, 1H), 3.81 (s, 3H),7.03 (d, J=8.48 Hz, 1H), 7.10-7.15 (m, 2H), 7.24-7.35 (m, 3H). ESI-MScalcd for C₂₆H₂₆Cl₂N₂O₄S: 532.10. Found (M+H⁺): 533.00. Anal. Calcd. ForC₂₆H₂₆Cl₂N₂O₄S.1.0H₂O: C, 56.62; H, 5.12; N, 5.08; S, 5.81. Found: C,56.89; H, 5.01; N, 5.35; S, 5.55.

Example C(50)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-pyridin-4-yl-4H-1,2,4-triazole-3-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) 8:1.30-1.68 (m, 8H), 1.82-2.10 (s, 2H),2.31-2.40 (m, 1H), 2.47-2.52 (m, 2H), 2.69-2.75 (m, 1H), 2.86-2.93 (m,1H), 3.71 (s, 3H), 6.90 (d, J=8.48 Hz, 1H), 7.02-7.06 (m, 1H), 7.19 (d,J=1.88 Hz, 1H), 7.64 (d, J=4.71 Hz, 2H), 8.48 (d, J=4.71 Hz, 2H). ESI-MScalcd for C₂₆H₂₇ClN₄O₄S: 526.1. Found (M+H⁺): 517.2. Anal. Calcd. ForC₂₆H₂₇ClN₄O₄S.0.4HOAc: C, 58.41; H, 5.23; N, 10.17; S, 5.82. Found: C,58.33; H, 5.57; N, 10.02; S, 5.76.

Example C(51)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-pyridin-4-yl-1,3,4-oxadiazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.26-1.62 (m, 8H), 1.92-1.98 (m, 2H),2.26-2.31 (m, 1H), 2.41-2.50 (m, 2H), 2.64-2.70 (m, 1H), 2.84-2.90 (m,1H), 3.65 (s, 3H), 6.85 (d, J=8.48 Hz, 1H), 7.02 (dd, J=8.48, 2.07 Hz,1H), 7.15 (d, J=2.07 Hz, 1H), 7.60 (d, J=5.84 Hz, 2H), 8.58 (s, 2H).ESI-MS calcd for C₂₆H₂₆ClN₃O₅S: 527.1. Found (M+H⁺): 528.1. Anal. Calcd.For C₂₆H₂₆ClN₃O₅S: C, 59.14; H, 4.96; N, 7.96; S, 6.07. Found: C, 59.13;H, 5.22; N, 7.62; S, 5.79.

Example C(52)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(5-fluoro-1H-benzimidazol-2-yl)thio]4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-fluoro-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.41-1.70 (m, 8H), 2.05-2.09 (m, 2H),2.39-2.44 (m, 1H), 2.56-2.61 (m, 2H), 2.63-2.67 (m, 1H), 2.87-2.91 (m,1H), 3.75-3.83 (m, 3H), 6.95-7.01 (m, 1H), 7.03 (d, J=8.59 Hz, 1H),7.10-7.15 (m, 2H), 7.27-7.28 (m, 1H), 7.31-7.35 (m, 1H). ESI-MS calcdfor C₂₆H₂₆ClFN₂O₄S: 516.1. Found (M+H⁺): 517.1. Anal. Calcd. ForC₂₆H₂₆ClFN₂O₄S.0.9H₂O: C, 58.47; H, 5.22; N, 4.91; S, 5.61. Found: C,58.84; H, 5.01; N, 4.64; S, 5.27.

Example C(53)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-methyl-1H-benzimidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-methyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.43-1.69 (m, 8H), 1.94-1.99 (m, 2H),2.35-2.37 (m, 1H), 2.40 (s, 3H), 2.52-2.60 (m, 3H), 2.70-2.76 (m, 1H),3.80 (s, 3H), 7.02 (d, J=8.67 Hz, 1H), 7.09 (d, J=1.88 Hz, 1 H), 7.12(brs, 1H), 7.24 (d, J=2.07 Hz, 1H), 7.26 (brs, 1H), 7.36 (d, J=8.29 Hz,1H). ESI-MS calcd for C₂₇H₂₉ClN₂O₄S: 512.2. Found (M+H⁺): 513.0. Anal.Calcd. For C₂₇H₂₉ClN₂O₄S.0.9HOAc: C, 60.99; H, 5.79; N, 4.94; S, 5.65.Found: C, 61.13; H, 5.81; N, 4.88; S, 5.59.

Example C(54)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-methyl-1H-benzimidazol-2-yl)thiol]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where4-methyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.44-1.68 (m, 8H), 1.95-2.00 (m, 2H),2.36-2.39 (m, 1H), 2.42 (s, 3H), 2.45-2.47 (m, 1H), 2.53-2.59 (m, 2H),2.71-2.75 (m, 1H), 3.80 (s, 3H), 7.00-7.06 (m, 2H), 7.09-7.15 (m, 2H),7.24-7.27 (m, 2H). ESI-MS calcd for C₂₇H₂₉C1N₂O₄S: 512.2. Found (M+H⁺):513.1. Anal. Calcd. For C₂₇H₂₉ClN₂O₄S.1.0H₂O: C, 61.06; H, 5.88; N,5.28; S, 6.04. Found: C, 60.89; H, 5.71; N, 5.17; S, 5.86.

Example C(55)2-({6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-1H-benzimidazole-5-carbonitrile

The title compound was prepared analogously to Example C(40), where2-mercapto-1H-benzimidazole-5-carbonitrile was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.54-1.74 (m, 8H), 2.11-2.17 (m, 2H),2.42-2.45 (m, 1H), 2.57-2.63 (m, 2H), 2.70-2.76 (m, 1H), 2.94-3.00 (m,1H), 3.82 (s, 3H), 7.04 (d, J=8.48 Hz, 1H), 7.14-7.17 (m, 1 H), 7.29 (d,J=2.07 Hz, 1H), 7.42-7.49 (m, 2H), 7.69 (s, 1H). ESI-MS calcd forC₂₇H₂₆C1N₃O₄S: 523.1. Found (M+H⁺): 524.1. Anal. Calcd. ForC₂₇H₂₆ClN₃O₄S.0.4H₂O: C, 61.04; H, 5.09; N, 7.91. Found: C, 61.27; H,5.42; N, 7.90.

Example C(56)2-({-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)nicotinonitrile

The title compound was prepared analogously to Example C(40), where2-mercaptonicotinonitrile was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.43-1.78 (m, 8H), 2.04-2.10 (m, 2H),2.40-2.45 (m, 1H), 2.63-2.69 (m, 2H), 2.78-3.00 (m, 2H), 3.81 (s, 3H),7.06 (d, J=8.48 Hz, 1H), 7.15-7.19 (m, 1H), 7.31 (d, J=1.88 Hz, 1H),7.52 (dd, J=8.19, 4.43 Hz, 1H), 8.18 (dd, J=8.19, 1.41 Hz, 1H), 8.82(dd, J=4.43, 1.41 Hz, 1H). ESI-MS calcd for C₂₅H₂₅C1N₂O₄S: 484.1. Found(M+H⁺): 485.0. Anal. Calcd. For C₂₅H₂₅C1N₂O₄S.0.4H₂O: C, 61.00; H, 5.28;N, 5.69; S, 6.51. Found: C, 60.90; H, 5.15; N, 5.87; S, 6.66.

Example C(57)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-[(5-Chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-chloro-1-methyl-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.39-1.70 (m, 8H), 2.21-2.27 (m, 2H),2.42-2.46 (m, 1H), 2.55-2.70 (m, 3H), 2.93-2.99 (m, 1H), 3.73 (s, 3H),3.82 (s, 3H), 7.01-7.04 (m, 2H), 7.13-7.20 (m, 2H), 7.29 (d, J=2.07 Hz,1H), 7.49 (d, J=8.48 Hz, 1H). ESI-MS calcd for C₂₇H₂₈Cl₂N₂O₄S: 546.1.Found (M+H⁺): 547.0. Anal. Calcd. For C₂₇H₂₈Cl₂N₂O₄S.0.4HOAc: C, 58.42;H, 5.22; N, 4.90; S, 5.61. Found: 58.25; H, 5.12; N, 4.88; S, 5.46.

Example C(58)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-hydroxy-1H-benzimidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where2-mercapto-1H-benzimidazol-4-ol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.26-1.55 (m, 8H), 1.77-1.80 (m, 2H),2.19-2.27 (m, 1H), 2.39-2.45 (m, 3H), 2.54-2.60 (m, 1H), 3.66 (s, 3H),6.54 (d, J=7.35 Hz, 1H), 6.77 (d, J=7.91 Hz, 1H), 6.86-6.97 (m, 3H),7.09 (d, J=2.07 Hz, 1H). HRMS calcd. For C₂₆H₂₈ClN₂O₅S (M+H⁺): 515.1402.Found: 515.1381.

Example C(59)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(5-ethoxy-1H-benzimidazol-2-yl)thio]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-ethoxy-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.33 (t, J=6.97 Hz, 3H), 1.41-1.68 (m, 8H),1.93-1.99 (m, J=17.33 Hz, 2H), 2.34-2.44 (m, 2H), 2.54-2.60 (m, 2H),2.71-2.77 (m, 1H), 3.80 (s, 3H), 4.02 (q, J=6.91 Hz, 2H), 6.88 (dd,J=8.76, 2.35 Hz, 1H), 6.94 (d, J=2.26 Hz, 1H), 7.02 (d, J=8.48 Hz, 1H),7.09-7.12 (m, 1H), 7.24 (d, J=1.88 Hz, 1H), 7.36 (d, J=8.67 Hz, 1H).ESI-MS calcd for C₂₈H₃₁ClN₂O₅S: 542.2. Found (M+H⁺): 543.1. Anal. Calcd.For C₂₈H₃₁ClN₂O₅S.0.4HOAc: C, 60.99; H, 5.79; N, 4.94; S, 5.65. Found:C, 61.05; H, 5.82; N, 4.62; S, 5.41.

Example C(60)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(5,6-dichloro-1-methyl-1H-benzimidazol-2-yl)thio]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5,6-dichloro-1-methyl-1H-benzimidazole-2-thiol was substituted in placeof 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.37-1.74 (m, 8H), 2.26-2.32 (m, 2H),2.41-2.45 (m, 1H), 2.57-2.63 (m, 2H), 2.67-2.73 (m, 1H), 2.98-3.03 (m,1H), 3.73 (s, 3H), 3.82 (s, 3H), 7.03 (d, J=8.48 Hz, 1H), 7.08 (s, 1H),7.15 (d, J=8.48 Hz, 1H), 7.28 (d, J=1.70 Hz, 1H), 7.85 (s, 1H). ESI-MScalcd for C₂₇H₂₇Cl₃N₂O₄S: 580.1. Found (M+H⁺): 581.0. Anal. Calcd. ForC₂₇H₂₇Cl₃N₂O₄S.0.3H₂O: C, 55.21; H, 4.74; N, 4.77; S, 5.46. Found: C,55.22; H, 4.76; N, 4.89; S, 5.20.

Example C(61)3-[(5-chloro-6-fluoro-1H-benzimidazol-2-yl)thiol]-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where5-chloro-6-fluoro-1H-benzimidazole-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.40-1.71 (m, 8H), 2.13-2.18 (m, 2H),2.40-2.45 (m, 1H), 2.56-2.62 (m, 2H), 2.70-2.76 (m, 1H), 2.95-3.01 (m,1H), 3.81 (s, 3H), 7.04 (d, J=8.48 Hz, 1H), 7.13-7.16 (m, 1 H), 7.25 (d,J=9.61 Hz, 1H), 7.29 (d, J=1.88 Hz, 1H), 7.37 (d, J=6.78 Hz, 1H). ESI-MScalcd for C₂₆H₂₅Cl₂FN₂O₄S: 550.1. Found (M+H⁺): 551.0. Anal. Calcd. ForC₂₆H₂₅Cl₂FN₂O₄S.0.3H₂O: C, 56.08; H, 4.63; N, 5.03; S, 5.76. Found: C,56.08; H, 4.86; N, 5.17; S, 5.80.

Example C(62):6-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-{[7-chloro-5-(trifluoromethyl)-1H-benzimidazol-2-yl]thio}-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol was substituted inplace of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ:1.42-1.68 (m, 8H), 1.92-1.96 (m, 2H),2.32-2.37 (m, 1H), 2.53-2.66 (m, 3H), 3.07-3.15 (m, 1H), 3.79 (s, 3H),7.00 (d, J=8.48 Hz, 1H), 7.07-7.11 (m, 1H), 7.22 (d, J=2.07 Hz, 1H),7.42 (d, J=1.13 Hz, 1H), 7.56 (s, 1H). ESI-MS calcd forC₂₇H₂₅Cl₂F₃N₂O₄S: 600.1. Found (M+H⁺): 610.0. Anal. Calcd. ForC₂₇H₂₅Cl₂F₃N₂O₄S.1.0H₂O: C, 52.35; H, 4.39; N, 4.52; S, 5.18. Found: C,52.06; H, 4.64; N, 4.80; S, 4.82.

Example C(63)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-onewas substituted in place of3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-oneand 5-chloro-1-methyl-1H-benzimidazole-2-thiol was substituted in placeof 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.37-1.71 (m, 8H), 2.07-2.19 (m, 2H),2.35-2.42 (m, 1H), 2.57-2.72 (m, 3H), 2.83-2.88 (m, 1H), 3.71 (s, 3H),3.75 (s, 3H), 3.86 (s, 3H), 6.71 (s, 1H), 7.01 (d, J=1.70 Hz, 1 H), 7.13(s, 1H), 7.16 (d, J=2.07 Hz, 1H), 7.45 (d, J=8.67 Hz, 1H). ESI-MS calcdfor C₂₈H₃₀Cl₂N₂O₅S: 576.1. Found (M+H⁺): 577.1. Anal. Calcd. ForC₂₈H₃₀Cl₂N₂O₅S.1.0H₂O: C, 56.47; H, 5.42; N, 4.70; S, 5.38. Found: C,56.86; H, 5.24; N, 5.05; S, 5.20.

Example C(64)6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one,where 4-bromo-2-fluoro-1-isopropoxybenzene was) was substituted in placeof3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-oneand 7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol wassubstituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.26 (d, J=6.03 Hz, 6H), 1.43-1.71 (m, 8H),2.16-2.22 (m, 2H), 2.39-2.42 (m, 1H), 2.53-2.69 (m, 3H), 2.70-2.75 (m,1H), 3.70 (s, 3H), 4.50-4.58 (m, 1H), 6.93-6.96 (m, 1H), 7.02-7.08 (m,2H), 7.11-7.15 (m, 2H), 7.41-7.44 (m, 1H). ESI-MS calcd forC₂₉H₃₂Cl₂N₂O₄S: 558.2. Found (M+H⁺): 559.1. Anal. Calcd. ForC₂₉H₃₂Cl₂N₂O₄S.1.0H₂O: C, 60.35; H, 5.94; N, 4.85; S, 5.56. Found: C,60.46; H, 5.95; N, 4.74; S, 5.52.

Step 1: Methyl2-chloro-5-cyclopentyl-7-(3-fluoro-4-isopropoxyphenyl)-5-hydroxy-3-oxoheptanoate

Methyl-2-chloroacetoacetate (2.0 mL, 16.2 mmol) was added to a cooled 0°C. suspension of NaH (0.65 g, 16.2 mmol, 60% dispersion in mineral oil)in THF (54 mL). After 15 min the solution was cooled to −40° C. andn-BuLi (10.0 mL, 16.2 mmol, 1.6M in hexanes) was added. The resultingdianion was stirred for an additional 30 min and then treated with asolution of 1-cyclopentyl-3-(3-fluoro-4-isopropoxyphenyl)propan-1-one(1.5 g, 5.4 mmol, compound was prepared analogously to Step 1 of ExampleA(82), where 4-(bromo)-2-fluoro-1-isopropoxybenzene was substituted inplace of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40°C., the reaction mixture was quenched with saturated NH₄Cl and extractedwith EtOAc. The organic layers were washed with brine, dried with Na₂SO₄and concentrated to an orange oil that was used without furtherpurification.

Step 2:3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

A solution of methyl2-chloro-5-cyclopentyl-7-(3-fluoro-4-isopropoxyphenyl)-5-hydroxy-3-oxoheptanoate(1.74 g, 4.1 mmol), and bis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol),dissolved in toluene (20 mL) were heated at reflux for 30 mins. Theresulting mixture was concentrated and purified by silica gelchromatography to give the title compound (0.80 g, 50% yield, twoSteps).

¹H NMR (300 MHz, CDCl₃): δ 1.33 (d, J=6.03 Hz, 6H), 1.45-1.80 (m, 10H),1.99-2.05 (m, 2H), 2.34-2.44 (m, 1H), 2.59-2.66 (m, 2H), 4.44-4.52 (m,1H), 6.78-6.91 (m, 3H).

Example C(65)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(9H-purin-8-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where9H-purine-8-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.37-1.68 (m, 8H), 2.04-2.10 (m, 2H),2.38-2.43 (m, 1H), 2.55-2.60 (m, 2H), 2.69-2.75 (m, 1H), 2.93-2.98 (m,1H), 3.78 (s, 3H), 7.03 (d, J=8.48 Hz, 1H), 7.15-7.19 (m, 1H), 7.28 (d,J=1.88 Hz, 1H), 8.62 (s, 1H), 8.72 (s, 1H). ESI-MS calcd forC₂₄H₂₅ClN₄O₄S: 500.1. Found (M+H⁺): 501.1. Anal. Calcd. ForC₂₄H₂₅ClN₄O₄S.1.2H₂O: C, 55.15; H, 5.28; N, 10.72; S, 6.14. Found: C,54.92; H, 5.28; N, 11.16; S, 6.01.

Example C(66)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(quinolin-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), wherequinoline-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.33-1.64 (m, 8H), 1.91-2.03 (m, 2H),2.13-2.20 (m, 1H), 2.38-2.49 (m, 2H), 2.55-2.61 (m, 1H), 2.73-2.79 (m,1H), 3.59 (s, 3H), 6.81 (d, J=8.48 Hz, 1H), 6.92-6.95 (m, 1 H),7.02-7.08 (m, 3H), 7.19-7.22 (m, 2H), 7.59-7.62 (m, 1H), 7.87 (d, J=8.85Hz, 1H). ESI-MS calcd for C₂₈H₂₈ClNO₄S: 509.1. Found (M+H⁺): 510.1.Anal. Calcd. For C₂₈H₂₈ClNO₄S.0.5H₂O: C, 64.79; H, 5.63; N, 2.70; S,6.18. Found: C, 64.52; H, 5.66; N, 2.68; S, 6.07.

Example C(67)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(7H-purin-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), where7H-purine-2-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.43-1.71 (m, 8H), 2.18-2.29 (m, 2H),2.60-2.76 (m, 4H), 2.88-2.94 (m, 1H), 3.82 (m, 3H), 7.03-7.36 (m, 3H),8.39-8.74 (m, 2H). ESI-MS calcd for C₂₄H₂₅C1N₄O₄S: 500.1. Found (M+H⁺):501.1. Anal. Calcd. For C₂₄H₂₅ClN₄O₄S.0.7H₂O: C, 56.12; H, 5.18; N,10.91; S, 6.24. Found: C, 55.87; H, 5.26; N, 10.73; S, 6.14.

Example C(68)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(quinazolin-4-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example C(40), wherequinazoline-4-thiol was substituted in place of5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

¹H NMR (300 MHz, DMSO-D₆) δ: 1.42-1.77 (m, 8H), 2.25-2.35 (m, 2H),2.61-2.77 (m, 4H), 2.96-3.02 (m, 1H), 3.83 (m, 3H), 7.07-7.10 (m, 1H),7.16-7.20 (m, 1H), 7.30 (s, 1H), 7.71-7.76 (m, 1H), 7.90-7.99 (m, 1H),8.21 (d, J=8.29 Hz, 1H), 8.49 (s, 1H). HRMS calcd. For C₂₇H₂₈ClN₂O₄S(M+H⁺): 511.1453. Found: 511.1443.

Example C(69)6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio]4-hydroxy-5,6-dihydro-2H-pyran-2-one

A mixture of3-chloro-6-cyclopentyl-6-{-[4-(difluoromethyl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione(200 mg, 0.514 mmol), from Step 1, below, and5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (93 mg, 0.514 mmol)in DMF (4 mL) was treated with triethylamine (52 mg, 0.514 mmol, 1equiv). The mixture stirred and heated at 55° C. for 4 h. The reactionwas cooled to room temperature, and the DMF removed in vacuo. Water andethyl acetate were added to the resinous material, resulting in theprecipitation of a solid. This was filtered, washed with ether, andallowed to air dry, affording 186 mg (68%) of the title product.

¹H NMR (DMF-d₇) δ 1.81-2.00 (m, 8H) 2.56-2.62 (m, 2H) 2.71 (s, 3H) 2.76(s, 3H) 2.80 (m, 1H) 3.07(m, 2H) 3.14 (d, J=6 Hz, 1H) 3.32 (d, J=18 Hz,1H) 7.40 (t, J=57 Hz, 1H), 7.24 (s, 1H) 7.66 (m, 2H) 7.84 (m, 1H,). MS(APCI) calcd for C₂₆H₂₇F₃O₃S: 532.58; MS found; (M+H⁺) 533.1. Anal.Calc'd for C₂₆H₂₇F₃O₃S: C, 58.64; H, 5.11; N, 10.52; S, 6.02. Found: C,58.26, 58.33; H, 5.25, 5.14; N, 10.69, 10.61; S, 5.78, 5.79.

Step 1:3-chloro-6-cyclopentyl-6-{-[4-(difluoromethyl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione

To a slurry of NaH (450 mg, 18.65 mmol) in dry THF (6 mL) at −40° C.under nitrogen was added a cold solution of methyl 2-chloroacetoacetate(2.67 g, 17.76 mmol) in 20 mL dry THF (20 mL) at such a rate that thetemperature was maintained within 5° C. of −40° C. When the addition wascomplete, the mixture was stirred at this temperature for an additional30 min, then cooled to −70° C. with a dry ice/acetone bath. Cold n-BuLi(9 mL, 2.08 M, 18.65 mmol) was slowly added via syringe, maintaining thetemperature at −70° C. The mixture was stirred for an additional 45 minat this temperature. A solution of1-cyclopentyl-3-[4-(difluoromethyl)-3-fluorophenyl]propan-1-one (4 g,14.8 mmol) in dry THF (20 mL) was added slowly via an addition funnel.The reaction was allowed to stir at −70° C. for 45 min, then warmed toroom temperature. After stirring for 2 h, the mixture was quenched with4M aqueous NH₄Cl (9.35 mL, 37.3 mmol), stirred for 5 min, thenconcentrated in vacuo. The oily residue was treated with water andextracted with CH₂Cl₂ (3×50 mL). The extract was dried over Na₂SO₄,filtered and concentrated to a orange resin. Purification by columnchromatography on silica gel and a gradient of 10% ethyl acetate/hexanesto 100% ethyl acetate afforded 3.5 g (8.32 mmol, 56%) of methyl2-chloro-5-cyclopentyl-7-[4-(difluoromethyl)-3-fluorophenyl]-5-hydroxy-3-oxoheptanoate.This hydroxyester intermediate was dissolved in toluene (20 mL), treatedwith bis(dibutylchlorotin)oxide (2.07 g, 3.75 mmol, 0.45 equiv), and themixture refluxed for 1 h. The solution was cooled to room temperature,the solvent removed in vacuo, and the resin filtered through a plug ofsilica gel, eluting with 5% MeOH/ethyl acetate. The fractions containingthe product were evaporated and recrystallized from ethyl ether,affording 437 mg (13.5% yield) of the title product.

Example C(70)8-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-1,7-dihydro-6H-purin-6-one

A solution of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionein anhydrous DMF (0.5 M, 160 μL, 0.08 mmol) was delivered by electronicpipette to a reaction vessel. To this was added a solution of6-hydroxy-8-mercaptopurine monohydrate in anhydrous DMF (0.5M, 160 μL,0.08 mmol, 1 equiv), and a solution of triethylamine in DMF (1M, 80 μL,0.08 mmol, 1 equiv). The reaction mixture was heated at 55+/−5° C. for16 h. The solvent was evaporated and the residue dissolved in DMSO tomake a final concentration of 0.0572 M, and the product purified by HPLCusing a Pecke Hi-Q 5 μm, 20×100 mm column with a 5-90% CH₃CN/0.05% TFAgradient. A run time of 8.1 min, a flow rate of 30.0 mL/min, and amonitoring wavelength at 260 nm were used.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.55-1.70 (m, 8H) 1.91 (m, 2H) 2.35 (m, 1H) 2.63 (m, 1H)2.50-2.60 (m, 2H) 2.75 (d, J=17.6 Hz, 1H) 2.98 (d, J=17.6 Hz, 1H) 3.80(s, 3H) 3.84 (s, 3H) 6.71 (s, 1H) 7.20 (s, 1H) 7.88 (s, 1H) 12.14 (s,1H). MS (APCI) calcd for C₂₅H₂₇C1N₄O₆S: 546.13; found [M+1]: 547.1.

Example C(71)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-phenyl-1H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-phenyl-1,2,4-triazole-5-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.55-1.74 (m, 8H) 1.90 (m, 1H) 2.35 (s, 1H) 2.62 (m, 1H)2.70 (d, J=17.9 Hz, 1H) 2.80 (d, J=17.6 Hz, 2H) 2.89 (d, J=17.9 Hz, 1H)3.70 (s, 3H) 3.78 (s, 3H) 6.64 (s, 1H) 7.15 (s, 2H) 7.32 (d, J=5 Hz, 1H)7.70 (s 1H) 7.78 (s, 1H). MS (APCI) calcd for C₂₈H₃₀ClN₃O₅S: 556.08;found M: 556.

Example C(72)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-methyl-1H-tetrazol-5-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-mercapto-1-methyltetrazole was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.50-1.69 (m, 8H) 1.92 (m, 2H) 2.37 (m, 1H) 2.50 (m, 1H)2.63 (m, 1H) 2.72 (d, J=17.9 Hz, 1H) 2.93 (d, J=17.9 Hz, 1H) 3.77 (s,3H) 3.84 (s, 3H) 3.97 (s, 3H) 6.71 (s, 1H) 7.18 (s, 1H). MS (APCI) calcdfor C₂₂H₂₇ClN₄O₅S: 494.99; found M=495.1.

Example C(73)6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-isopropyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-chloro-1-isopropyl-2-mercaptobenzimidazole was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.56 (s, 3H) 1.57 (s, 3H) 1.60-1.74 (m, 8H) 2.13 (m, 1H)2.29 (m, 1H) 2.35 (m, 1H) 2.50 (m, 1H) 2.63 (m, 1H) 2.74 (d, J=17.3 Hz,1H) 2.97 (d, J=17.3 Hz, 1H)3.74 (s, 3H) 3.86 (s, 3H) 4.80 (m, 1H) 6.71(s, 1H) 6.91 (s, 1H) 7.11 (dd, J=8.65, 2.06 Hz, 1H) 7.16 (s, 1H) 7.63(d, J=8.79 Hz, 1H). MS (APCI) calcd for C₃₀H₃₄Cl₂N₂O₅S: 605.58; foundM=605.0.

Example C(74)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[4-hydroxy-6-(trifluoromethyl)pyrimidin-2-yl]thio}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where4-hydroxy-6-(trifluoromethyl)pyrimidine-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.52-1.68 (m, 8H) 1.84 (m, 1H) 2.02 (m, 1H) 2.35 (s, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (s, 1H) 2.80-2.88 (m, 2H) 3.77 (s,3H) 3.83 (s, 3H) 6.52 (s, 1H) 6.70 (s, 1H) 7.12 (s, 1H). MS (APCI) calcdfor C₂₅H₂₆ClF₃N₂O₆S: 575.00; found M=575.0.

Example C(75)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.55-1.73 (m, 8H) 1.92 (m, 1H) 2.11 (m, 1H) 2.35 (m, 1H)2.50 (m, 1H, buried under dmso peak) 2.81 (d, J=17.6 Hz, 1H) 3.46 (m,2H) 3.71 (s, 3H) 3.78 (s, 3H) 6.61 (s, 1H) 7.12 (s, 1H) 7.38 (m, 1H)8.08 (m, 1H) 8.59 (d, J=5.2 Hz, 1H) 9.02 (s, 1H). MS (APCI) calcd forC₂₇H₂₉ClN₄O₅S: 557.07; found M=557.0.

Example C(76)3-[(5-amino-1-methyl-1H-benzimidazol-2-yl)thio]-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-Amino-1-methyl-1H-benzimidazole-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO [2.5 ppm] and H₂O[3.35 ppm]) δ 1.60 (m, 8H) 1.88 (m, 2H) 2.62 (m, 1H) 2.79 (d, J=17.86Hz, 1H) 3.78 (m, 1H) 6.71 (s, 1H) 6.88 (m, 1H) 7.12 (s, 1H) 7.48 (d,J=8.79 Hz, 1H). MS (APCI) calcd for C₂₈H₃₂ClN₃O₅S: 558.09; foundM=558.1.

Step 1: 6-amino-1H-benzimidazole-2-thiol

N¹-methylbenzene-1,2,4-triamine (Le Bris, M. T. Bull. Soc. Chim Fr 1976,5, 921) (10.91 g, 40 mmol) in EtOH (75 mL) and H₂O (12 mL) and potassiumo-ethyl dithiocarbonate (10.47 g, 64.01 mmol) were placed in a 250 mL3-necked round bottomed flask, outfitted with a mechanical overheadstirrer and N2 flow. The resulting suspension was stirred for 15 min atroom temperature. K2CO3 (8.36 g, 60.50 mmol) was added to the pot andthe reaction mixture refluxed for 18 h. Warm water (150 mL, 80° C.) wasadded to the reaction mixture along with an 8:5 acetic acid/watersolution (27 mL) to bring the pH to 5. The reaction mixture was allowedto cool to room temperature over 2 h and then was suction filtered. Thefiltrate (filtrate A) was concentrated to half the volume (250 mL to 125mL) by heating, then allowed to cool to room temperature over theweekend.

The solid obtained from the filtration was dissolved in 8% NaOH (50 mL)and filtered to remove any undissolved solids. This filtrate was broughtto pH 5 by the addition of glacial acetic acid and stirred for 1.5 h atroom temperature. The solution was filtered and washed with water togive Filtrate B.

Filtrate A formed a sticky black solid on the bottom and sides of theflask. The liquid (Filtrate A) was decanted off and the solid wasdissolved in 8% NaOH (150 mL) and filtered to remove any undissolvedsolids. The filtrate (Filtrate C) was acidified to pH 5 using glacialacetic acid (25 mL) and stirred at room temperature for 2 h. It wasfiltered again and washed with water, then concentrated to half itsvolume (225 mL to 115 mL). Filtrates A, B and C were combined andconcentrated by heating. The solution was suction filtered and washedwith H₂O (30 mL). A dark violet solid was obtained and dried in a vacuumoven affording 1.25 g (15.8%) of the desired product.

¹H NMR (DMSO-d₆) d 3.53 (s, 3H); 5.03 (broad s, 2H); 6.94 (s, 1H);6.43-6.46 (d, J=9 Hz, 1H); 6.98-7.01 (d, J=9 Hz, 1H); 12.23 (broad s,1H). MS (APCI) calcd for C₈H₉N₃S: 179.2; found (M+H⁺) 180.0.

Example C(77)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-6cyclopentyl-4-hydroxy-3-[(5-pyridin-3-yl-1H-imidazol-2-yl)thio]-5,6-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-pyridin-3-yl-1H-imidazole-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.40-1.71 (m, 8H) 1.91 (m, 1H)) 2.02 (m, 1H)2.36 (m, 1H) 2.49 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.72 (d,J=17.6 Hz, 1H) 2.94 (d, J=17.9 Hz, 1H) 3.72 (s, 3H) 3.79 (s, 3H) 6.61(s, 1H) 7.08 (s, 1H) 7.58 (m, 1H) 7.95 (s, 1H) 8.23 (m., 1H) 8.54 (d,J=4.67 Hz, 1H) 8.92 (s, 1H). MS (APCI) calcd for C₂₈H₃₀ClN₃O₅S: 556.08;found M=556.1.

Example C(78)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3[(3-methylpyrazin-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-methylpyrazine-2-thiol was used in place of 6-hydroxy-8-mercaptopurinemonohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.54-1.71 (m, 8H) 2.05 (m, 1H) 2.18 (m, 1H)2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.75 (d,J=17.6 Hz, 1H) 2.95 (d, J=17.3 Hz, 1H) 3.30 (s, 3H, overlap with H₂O)3.74 (s, 3H) 3.86 (s, 3H) 6.72 (s, 1H) 7.10 (s, 1H) 7.84 (d, J=2.20 Hz,1H) 8.11 (d, J=2.75 Hz, 1H). MS (APCI) calcd for C₂₅H₂₉ClN₂O₅S: 505.03;found M=505.0.

Step 1: 3-methylpyrazine-2-thiol

Sodium hydrogen sulfide dihydrate (139.7 g, 1.58 mol),2-chloro-3,(5),(6)-methylpyrazine (with 80% of 3-methyl isomer) (65.0 g,0.51 mol) and 1,3-propanediol (300 mL) were added to a 3-L roundbottomed flask, which was equipped with a magnetic stir bar, a condenserand a thermometer. The reaction mixture was heated for 1.5 h at 110-130°C. After cooling to room temperature, the inorganic salt was filteredand washed with methanol (200 mL). The combined filtrate wasconcentrated in vacuo, (10-20 mmHg/140-120° C.). Water (200 mL) wasadded to the residue and aqueous NaOH was used to adjust from pH 1 to pH14. Insoluble material was filtered and the filtrate was adjusted to pH5-6. The yellow solid was filtered, washed with water (2×100 mL) andlyophilized to yield 44 of a mixture of isomers of the desired product,of which contained 80% of the 3-methyl isomer. The mixture was dissolvedin 4 L of hot isopropanol/ethanol (1:1). Upon cooling to roomtemperature, the yellow crystallized impurity was filtered. Afterevaporating the filtrate under reduced pressure, the desired product wasobtained as a yellow solid. (25.0 g, 39% yield, 85% pure).

¹H NMR (DMSO-d₆): d 2.5 (s, 3H) 7.54 (s, 1H) 7.71 (d, J=3.0 Hz, 1H)14.15 (broad s, 1H). MS (APCI) calcd for C₅H₆N₂S: 126.03; found (M+H⁺):127.0.

Example C(79)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[5-(3-methoxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-(3-methoxyphenyl)-4-methyl-4H-1,2,4-triazole-3-thiol was used in placeof 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.53-1.74 (m, 8H) 1.91 (m,Hz, 2H) 2.35 (m, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.70 (d, J=17.9 Hz, 1H)2.92 (d, J=17.6 Hz, 1H) 3.67 (s, 3H) 3.77 (s, 3H) 3.80 (s, 3H) 3.83 (s,3H) 6.69 (s, 1H) 7.11 (m, 1H) 7.20 (s, 2H) 7.45 (t, J=8.2 Hz, 1H). MS(APCI) calcd for C₃₀H₃₄ClN₃O₆S: 600.13; found M=600.1.

Example C(80)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-hydroxy-4-isopropyl-4H-1,2,4-triazol-3-yl)thiol-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where4-isopropyl-5-mercapto-4H-1,2,4-triazol-3-ol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.35 (s, 3H) 1.37 (s, 3H) 1.54-1.69 (m, 8H)1.80 (m, 1H) 1.91 (m, 1H) 2.06 2.34 (m, 1H) 2.50 (m, 1H, overlap withdmso) 2.63 (m, 1H) 2.74 (d, J=15.0 Hz, 1H) 2.85 (d, J=15.0 Hz, 1H) 3.77(s, 3H) 3.84 (s, 3H) 4.31 (m, 1H) 6.70 (s, 1H) 7.13 (s, 1H) 11.52 (s,2H). MS (APCI) calcd for C₂₅H₃₂ClN₃O₆S: 538.06; found M=538.1.

Example C(81)6-[2-(5-chlor-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3{[5-(4-hydroxyphenyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where4H-mercapto-5(4-hydroxyphenyl)-[1,2,4]triazole was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.50-1.72 (m, 8H) 1.89 (m, 2H) 2.35 (m, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.79 (d, J=17.9 Hz, 1H)3.73 (s, 3H) 3.81 (s, 3H) 6.66 (s, 1H) 6.70 (s, 1H) 6.72 (s, 1H) 7.14(s, 1H) 7.56 (s, 2H). MS (APCI) calcd for C₂₈H3₀ClN₃O₆S: 572.08; foundM=572.2

Example C(82):6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₈, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.55-1.73 (m, 8H) 2.03 (m, 1H) 2.11 (m, 1H)2.35 (m, 1H) 2.56 (m, 1H) 2.62 (m, 1H) 2.75 (d, J=17.6 Hz, 1H) 2.95 (d,J=17.6 Hz, 1H) 3.75 (s, 2H) 3.84 (s, 3H) 6.69 (s, 1H) 7.10 (d, J=6.9 Hz,1H) 7.19 (s, 1H) 8.69 (d, J=6.9 Hz, 1H). MS (APCI) calcd forC₂₆H₂₉ClN₄O₅S: 545.06; found M=545.2.

Step 1: 4-methyl-2-methylsulfanyl-pyrimidine

Based on a reported procedure (Ishizumi, K.; Kojima, A.; Antoku, F. ChemPharm Bull 1991, 39, 2288). Sodium hydroxide (92.5 g, 2.31 mol) wasadded to a suspension of 2-mercapto-4-methyl pyrimidine hydrochloride(150 g, 0.93 mol) in water (1.5 L). Methyl iodide (78.9 ml, 1.39 mol)was rapidly added to the clear solution (solution temp. <20° C.). Afterovernight stirring, diethyl ether (400 mL), the organic layer wasseparated and the aqueous layer was extracted with diethyl ether (4×200ml) all organic layers were combined, washed with 5% aq. NaOH solution(100 ml), brine (200 ml, 2 times), and dried (MgSO₄), concentrated invacuo to afford 119.3 g of crude material (95% pure by NMR) which wasused in the next step without purification.

¹H NMR (CDCl₃, 300 MHz) 6, ppm: 2.46 (s, 3H), 2.56 (s, 3H), 6.82 (d, J=5Hz, 1H,), 8.37 (d, J=5 Hz 1H).

Step 2: (4-methyl-pyrimidin-2-yl)-hydrazine

Based on a reported procedure (Vanderhaeghe, Claesen, Bull. Soc. Chim.Belg. 1959, 68, 30). Hydrazine monohydrate (334.7 ml, 6.90 mmol) wasadded in one portion to a solution of4-Methyl-2-methylsulfanyl-pyrimidine (357.9 g, 2.55 mol) in abs. EtOH(890 ml). The resulting mixture was refluxed for 50 h, then hydrazinemonohydrate (200 ml) was added and refluxing was continued for 50 h (thereaction was monitored by ¹H NMR). Then it was cooled to 0° C. tocrystallize and 213 g of crude product was isolated by filtration.Recrystallization from ethanol gave the title compound (184.7 g, 59%) asa white solid.

¹H NMR (CDCl₃, 300 MHz) δ, ppm: 2.40 (s, 3H), 4.00 (broad, 2H), 6.512(d, 1H, 5 Hz), 7.03 (broad, 1H), 8.24 (d, 1H, 5 Hz).

Step 3: Sodium 7-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate

The title compound was prepared by a modification or a reportedprocedure (Shirakawa, K. Yakugaku Zasshi 1960, 80, 1542. A solution of(4-Methyl-pyrimidin-2-yl)-hydrazine (140 g, 1.13 mol), sodium hydroxide(45 g, 1.13 mol) and carbon disulfide (67.7 ml, 1.13 mol) in 50% aqueousethanol (900 ml) was refluxed for 6 hours. The resulting mixture wascooled to ambient temperature and 54.7 g the yellow solid formed wasisolated (54.7 g). It was recrystallized from 50% aqueous ethanol anddried at 40° C./1 Torr for 10 hours to give 44 g (18%) of sodium5-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate, 85% pure byELSD and ¹H NMR.

The initial mother liquid was kept at 0° C. for 2 days. The crystallizedorange solid was isolated by filtration, dried for 10 h at 40° C./1 Torrto give 68.1 g (27%) of the title compound, sodium7-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate, used in Step 4,below. ¹H NMR (DMSO-d₆, 300 MHz) δ, ppm: 2.44 (s, 3H), 6.60 (d, 1H, 7Hz), 8.29 (d, 1H, 7 Hz).

Step 4: 5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol

The title compound was synthesized from7-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate (from Step 3,above) using the procedure described for the synthesis of7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thio][Step 2 in the AG-101578example], to give the crude product in 77% yield. Two recrystallizationsfrom 50% aqueous ethanol provided 99% pure (¹H NMR and ELSD) material in46% yield. ¹H NMR (DMSO-d₆, 300 MHz) 6, ppm: 2.58 s, 3H), 7.34 (d, 1H, 7Hz), 8.99 (d, 1H, 7 Hz), 14.10 (broad, 1H).”

Example C(83):6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-3-({5-[dimethylamino)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}thio)-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol was used inplace of 6-hydroxy-8-mercaptopurine monohydrate. ¹H NMR (500 MHz,DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O (3.35 ppm) peakareas) d ppm 1.59 (m, 8H) 1.91 (m, 2H) 2.36 (m, 1H) 2.62 (m, 1H) 2.73(d, J=17.58 Hz, 1H) 2.86 (s, 9H) 2.91 (d, J=17.86 Hz, 1H) 3.63 (s, 1H)3.80 (d, J=3.02 Hz, 1H) 3.84 (s, 1H) 4.52 (s, 3H) 6.71 (s, 1H) 7.20 (s,1H). MS (APCI) calcd for C₂₆H₃₅ClN₄O₅S: 551.10; found M=551.2.

Step 1: 5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol

N,N-dimethylglycine hydrazide hydrochloride (50 g, 0.263 mol) wasstirred for 5 min in EtOH (525 mL). To this suspension was added Cs2CO3(62.5 g, 0.192 mol) and the mixture was stirred at room temperature for15 min. Methyl isothiocyanate (19.25 g, 0.263 mol) in EtOH (270 mL) wasadded to the pot and the reaction mixture was brought to reflux. Thereflux condenser was removed and the EtOH was allowed to evaporate underatmospheric pressure (oil bath temperature 105-110° C.) over 3 h to givea purple paste. The reaction was removed from heat and allowed to sit atroom temperature overnight (18 h), during which time the paste became asolid. The solid was mixed with CH₂Cl₂ (1.5 L) and filtered. The organicfiltrate was concentrated under reduced pressure to give 31 g of a crudeyellow oil. The oil was purified by column chromatography through silicagel, eluting with 4:1 CH₂Cl₂/MeOH to afford 15.3 g (34.9%) of thedesired product.

¹H NMR (DMSO-d₆) d 2.17 (s, 6H) 3.46 (s, 5H) 13.57 (s, 1H). MS (APCI)calcd for C₆H₁₂N₄S: 172.25; found (M−H+) 171.1.

Example C(84)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylthio-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.55-1.72 (m, 8H) 2.08 (m, 2H) 2.35 (m, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.78 (d, J=17.9 Hz, 1H)2.96 (d, J=17.6 Hz, 1H) 3.76 (s, 3H) 3.85 (s, 3H) 6.70 (s, 1H) 7.20 (m,1H, overlap) 7.21 (s, 1H) 7.22 (m, 1H, overlap) 8.75 (dd, J=4.4, 1.7 Hz,1H) 8.87 (dd, J=6.9, 1.7 Hz, 1H). MS (APCI) calcd for C₂₅H₂₇ClN₄O₅S:531.03; found M=531.1.

Step 1: [1,2,4]triazolo[1,5-a]pyrimidine-2-thiol

The title compound was prepared from malonodialdehydebis(dimethylacetal) and 3-amino-5-mercapto-1,2,4-triazole as previouslydescribed by M. Künstlinger and E. Breitmaier in Synthesis, 1983, 4447.

¹H NMR (DMSO-d₆) d 7.07 (dd, J=6.8, J=3.8, 1H) 8.63 (d, J=6.8, 1H) 8.76(s, 1H). MS (APCI) calcd for C₅H₄N₄S: 152.18; found (M=H⁺) 153.0.

Example C(85)6-[-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where4-methyl-5-(3-pyridyl)-4H-1,2,4-triazole-3-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d ppm 1.52-1.69 (m, 8H) 1.92 (m, 2H) 2.37 (m, 1H)2.5 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.73 (d, J=17.6 Hz, 1H) 2.94(d, J=17.9 Hz, 2H) 3.70 (s, attenuation due to proximity to H₂O peak)3.8 (s, attenuation due to proximity to H₂O peak) 6.70 (s, 1H) 7.21 (s,1H) 7.59 (dd, J=7.7, 4.7 Hz, 1H) 8.12 (d, J=8.5 Hz, 1H) 8.73 (d, J=4.1Hz, 1H) 8.89 (s, 1H). MS (APCI) calcd for C₂₈H₃₁ClN₄O₅S: 571.09; foundM=571.1.

Example C(86)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[5-methyl-4-(2-morpholin-4-ylethyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where5-methyl-4-(2-morpholin-4-ylethyl)-4H-1,2,4-triazole-3-thiol was used inplace of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d ppm 1.50 (m, 9H) 1.83 (m, 2H) 2.33 (m, 2H) 2.42(m, 1H) 2.63 (m, 1H) 2.78 (d, J=16.5 Hz, 1H) 3.27 (s, 4H) 3.42 (s, 3H)3.53 (m, 3H) 3.82 (d, J=15.0 Hz, 1H) 4.45 (m, 2H) 6.71 (s, 2H) 7.13 (s,1H). MS (APCI) calcd for C₂₉H₃₉ClN₄O₆S: 607.17; found M=607.1.

Step 1: 5-methyl-4-(2-morpholin-4-ylethyl)-4H-1,2,4-triazole-3-thiol

The title compound was prepared by a modification of a procedurereported for related compounds: Henichart, J. P.; Bernier, J. L.Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50mL) was placed in a 200 mL 3-necked round bottomed flask outfitted witha magnetic stir bar and a reflux condenser. 2-morpholinoethylisothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to thepot. The mixture was refluxed, under N₂, for 6 h. The reaction wascooled to room temperature and the solvent removed on the rotovap. Theresulting resin was dissolved in minimal ethanol and ether. A whitesolid precipitated out, was filtered and washed with cold ether. Thefiltrate, containing uncyclized intermediate, was concentrated anddissolved in xylenes. The mixture was refluxed under N2 for 8 h, thenallowed to sit at room temperature, under N2. for 48 h. A white solidformed, was filtered and washed with cold ether. The first and secondbatches of white solid were combined to yield 7.33 g (64%) of thedesired product.

¹H NMR (DMSO-d₆): d 2.33 (s, 3H) 2.41 (m, 4H) 2.55 (m, 2H) 3.52 (m, 4H)3.99 (t, 2H, J=6) 13.41 (s, 1H). MS (APCI) calcd for C₉H₁₆N₄OS: 228.32;found (M+H⁺) 229.1.

Example C(87)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.40-1.74 (m, 8H) 2.09 (m, 1H) 2.18 (m, 1H)2.29 (s, 3H) 2.35 (m, 1H) 2.63 (m, 1H) 2.69 (m, 1H) 2.75 (d, J=17.6 Hz,1H) 2.86 (m, 1H) 2.98 (d, J=17.9 Hz, 1H) 3.75 (s, 2H) 3.85 (m, 3H) 6.70(s, 1H) 7.19 (s, 1H) 8.48 (s, 1H) 8.64 (d, J=2.2 Hz, 1H). MS (APCI)calcd for C₂₆H₂₉ClN₄O₅S: 545.06; found M=545.2.

Step 1: 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol

The title compound was prepared from 3-ethoxymethacrolein and3-amino-5-mercapto-1,2,4-triazole as previously described by M.Künstlinger and E. Breitmaier in Synthesis, 1983, 44-47.

¹H NMR (DMSO-d₆) d 2.31 (s, 1H) 8.45 (s, 1H) 8.68 (s, 1H). MS (APCI)calcd for C₆H₆N₄S: 166.21; found (M+H⁺) 167.0.

Example C(88)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-3-[(4,6-dimethyl-4H-1,2,4-triazol-3-yl)thio]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where4,5-dimethyl-4H-1,2,4-triazole-3-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.84 (m, 3H) 2.18 (m, 1H)2.32 (m, 2H) 2.38 (s, 3H) 2.61 (d, J=17.9 Hz, 1 H) 2.82 (d, J=17.3 Hz,1H) 3.56 (s, attenuation due to proximity to H₂O peak) 3.78 (s,attenuation due to proximity to H₂O peak) 3.84 (s, 3H) 6.71 (s, 1H) 7.12(s, 1H). MS (APCI) calcd for C₂₄H₃₀ClN₃O₅S: 508.04; found M=508.1.

Step 1: 4,5-dimethyl-4H-1,2,4-triazole-3-thiol

Acetic hydrazide (7.4 g, 100 mmol) in ethanol (75 mL) was placed in a200 mL 3-necked round bottomed flask outfitted with a magnetic stir barand a reflux condenser. Methyl isothiocyanate (7.3 g, 100 mmol) inethanol (75 mL) was added to the pot. The mixture was refluxed, underN₂, for 6 h. The reaction was cooled to room temperature and the solventremoved on the rotovap. The resulting wet solid was triturated withether and filtered to give a sticky, yellow solid. This solid wastriturated with hot CH₂Cl₂/ethyl acetate (1:1), which afforded a whitesolid of the uncyclized intermediate. The solid and all liquidsassociated with the reaction were combined, dissolved in ethanol.Aqueous NaOH (1 M, 50 mL) was added and the mixture refluxed under N₂for 1 h. Acetic acid was used to acidify to a pH of 4-5. The mixture wasthen cooled on an ice bath to facilitate precipitation. White solidformed, was filtered and washed with ether. (repeated thecrystallization process three times with mother liquors). Combined allsolids collected and chromatographed through silica gel, eluting with14% MeOH/ethyl acetate. The collected fractions were concentrated,washed with ether and filtered to yield 5.02 g (38.9%) of the desiredproduct.

¹H NMR (DMSO-d₆): d 2.27 (s, 3H) 3.37 (s, 3H) 13.36 (broad s, 1H). MS(APCI) calcd for C₄H₇N₃S: 129.18; found (M+H⁺) 130.0.

Example C(89) Methyl5-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-4-methyl-4H-1,2,4-triazole-3-carboxylate

The title compound was prepared as described in Example C(70), wheremethyl 5-mercapto-4-methyl-4H-1,2,4-triazole-3-carboxylate was used inplace of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.51-1.67 (m, 8H) 1.88 (m, 2H) 2.36 (m, 1H) 2.5(m, 1H, overlap with dmso) 2.63 (m, 1H) 2.73 (d, J=17.6 Hz, 1H) 2.90 (d,J=17.6 Hz, 1H) 3.77 (s, 3H) 3.81 (s, 3H) 3.85 (s, 3H) 3.87 (s, 3H) 6.70(s, 1H) 7.16 (s, 1H). MS (APCI) calcd for C₂₅H₃₀ClN₃O₇S: 552.05; foundM=552.1.

Step 1: methyl hydrazino(oxo)acetate

This compound was prepared as described: Smuszkovicz, J.; Greig, M. E.J. Med Pharm. Chem. 1961, 4, 259). From 1.08 mol of dimethyl oxalate,51.7 g (44%) of the title product was obtained.

¹H NMR (DMSO-d₆) d 3.75 (s, 3H) 4.63 (broad s, 2H) 10.24 (broad s, 1H).MS (APCI) calcd for C₃H₆N₂O₃: 118.09; found (M+H⁺) 119.1.

Step 2: methyl 5-mercapto-4-methyl-4H-1,2,4-triazole-3-carboxylate

Methyl isothiocyanate (24 g, 0.328 mol) in MeOH (100 mL) was added to astirred solution of methyl hydrazino(oxo)acetate (35 g, 0.296 mol) inMeOH (350 mL) and the reaction mixture refluxed for 24 h. TLC(MeOH/CH₂Cl₂, 1:9) indicated no starting material present, intermediateproduct appeared on TLC as a single spot, Rf=0.44. Cs₂CO₃ (24 g, 0.74mol) was added to the hot reaction mixture, cautiously, as the reactionwas exothermic. The reaction mixture was cooled down to room temperatureand then filtered. The filtrate was concentrated to wet yellow paste.The paste was triturated with CH₂Cl₂ and filtered. The solid materialwas dried in the vacuum oven at 30° C. to afford 43.1 g of product. Themother liquor was concentrated, then triturated with cold CH₂Cl₂ andfiltered and dried in the vacuum oven at 30° C. to give an additional 6g of product. The two batches were combined to yield 49.1 g (95.8%) ofdesired product. ¹H NMR (DMSO-d₆) d 3.63 (s, 3H) 3.84 (s, 3H) 13.83(broad s, 1H). MS (APCI) calcd for C₅H₇N₃O₂S: 173.19; found (M+H⁺)174.0.

Example C(90)6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[4-methyl-5-(2-morpholin-4-ylethyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), wheremethyl-5-(2-morpholin-4-ylethyl)-4H-1,2,4-triazole-3-thiol was used inplace of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.46-1.66 (m, 12H) 1.88 (dd, J=9.8, 6.7 Hz, 4H)2.34 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.69 (d,J=17.9 Hz, 2H) 2.87 (d, J=17.6 Hz, 2H) 3.16 (t, J=7.55 Hz, 2H) 3.80 (s,attenuation due to proximity to H₂O peak) 3.82 (m, 2H) 3.84 (s, 6H) 6.71(s, 1H) 7.19 (s, 1H). MS (APCI) calcd for C₂₉H₃₉ClN₄O₆S: 607.17; foundM=607.1.

Step 1: 3-morpholin-4-ylpropanohydrazide

Hydrazine (64.1 g, 2 mol) was added dropwise, over 8-10 min, to methyl3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture wasrefluxed for 16 h. The excess hydrazine was removed under reducedpressure and the material was dried in vacuo at room temperature for 16h to give the crude product as an oil. The ¹H NMR showed the presence ofhydrazine, so the crude material was dried using a lyophilizer. Then theoil was refluxed in benzene/water (using a Dean-Stark distillingreceiver). The benzene was then removed under reduced pressure, and theproduct was triturated with petroleum ether. After sitting in petroleumether at room temperature for 16 h, the oil solidified. The petroleumether was decanted and the solid was dried under house vacuum at roomtemperature to give the desired product (21.5 g, 61.4%), which was usedwithout further purification.

Step 2: 4-methyl-5-(2-morpholin-4-ylethyl)-4H-1,2,4-triazole-3-thiol

Prepared according to a procedure reported for related compounds:Henichart, J. P. et al. J. Het Chem. 1977, 14, 615. Methylisothiocyanate (9.08 g, 0.124 mol) in EtOH (50 mL) was added at roomtemperature to a stirred solution of 3-morpholin-4-ylpropanohydrazide(21.5 g, 0.124 mol) in EtOH (200 mL). The mixture was refluxed for 8 h,then removed from heat and stirred at room temperature for 16 h. TheEtOh was removed under reduced pressure to give the crude material as ayellow oil. The oil was purified by column chromatography through silicagel, eluting with CH₂Cl₂/MeOH to afford the title compound. (6 g,21.2%).

¹H NMR (DMSO-d₆) d 2.42 (m, 4H) 2.64 (m, 2H) 2.85 (m, 2H; 3.43 (s, 3H)3.55 (m, 4H) 13.47 (s, 1H).

MS (APCI) calcd for C₉H₁₆N₄OS: 228.32; found (M−H+) 227.1.

Example C(91) 36-[2-(3-chlor-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(6-hydroxy-7H-purin-8-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.54-1.69 (m, 9H) 2.03 (m, 2H) 2.35 (m, 1H)2.58 (m, 1H) 2.63 (m, Hz, 1H) 2.76 (d, J=17.6 Hz, 1H) 2.96 (d, J=15.0Hz, 1H) 3.80 (s, 3H) 7.05 (d, J=8.5 Hz, 1H) 7.24 (dd, J=8.5, 17 Hz, 1H)7.30 (d, J=1.7 Hz, 1H) 7.90 (d, J=3.6 Hz, 1H) 12.15 (broad s, 2H). MS(APCI) calcd for C₂₄H₂₅ClN₄O₅S: 517.00; found M=517.1.

Example C(92)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.53-1.69 (m, 8H) 2.03 (m, 1H) 2.11 (m, 1H)2.35 (m, 1H) 2.57 (m, 1H) 2.63 (m, 1H) 2.82 (d, J=17.6 Hz, 1H) 2.96 (d,J=15.0 Hz, 1H) 3.77 (s, 3H) 6.95 (d, J=8.5 Hz, 1H) 7.09 (d, J=8.5 Hz,1H) 7.23 (d, J=1.4 Hz, 1H) 7.41 (m, 1H) 8.13 (s, 1H) 8.60 (d, J=4.1 Hz,1H) 9.03 (s, 1H). MS (APCI) calcd for C₂₆H₂₇ClN₄O₄S: 527.04; foundM=527.0.

Example C(93) Ethyl2-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate

The title compound was prepared as described in Example C(70), whereethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate was usedin place of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.34 (t, J=7.14 Hz, 3H) 1.55-1.74 (m, 8H) 2.07(m, 1H) 2.16 (m, 1H) 2.35 (m, 1H) 2.5 (m, 1H, overlap with dmso) 2.63(m, 1H) 2.78 (d, J=17.6 Hz, 1H) 2.98 (d, J=17.6 Hz, 1H) 3.72 (s, 3H)3.82 (s, 3H) 4.37 (q, J=7.1 Hz, 2H) 6.67 (s, 1H) 7.19 (s, 1H) 9.09 (d,J=2.2 Hz, 1H) 9.22 (d, J=2.2 Hz, 1H). MS (APCI) calcd for C₂₈H₃₁ClN₄O₇S:603.09; found M=603.1.

Step 1: ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate

The title compound was prepared by reaction of(ethoxycarbonyl)malonialdehyde with 3-amino-5-mercapto-1,2,4-triazole aspreviously described by M. Künstlinger and E. Breitmaier in Synthesis,1983, 4447. ¹H NMR (DMSO-d₆) d 1.35 (t, J=6.99, 1H) 4.39 (q, J=6.80, 1H)9.10 (s, 1H) 9.55 (s, 1H). MS (APCI) calcd for C₈H₈N₄O₂S: 224.24; found(M+H⁺) 225.0.

Example C(94) Ethyl2-({6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate wasused in place of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.34 (t, J=7.1 Hz, 3H) 1.55-1.74 (m, 8H) 2.07(m, 1H) 2.22 (m, 2H) 2.63 (d, J=8.2 Hz, 2H) 2.75 (d, J=17.6 Hz, 2H) 3.00(d, J=15.0 Hz, 1H) 3.81 (s 3H) 4.38 (m, 2H) 7.06 (t, J=8.8 Hz, 1H) 7.25(s, 1H) 7.27 (s, 1H) 7.30 (m, 1H) 9.13 (s, 1H) 9.26 (s, 1H). MS (APCI)calcd for C₂₇H₂₉ClN₄O₆S: 573.07; found M=573.1.

Example C(95)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(7-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in placeof 6-hydroxy-8-mercaptopurine monohydrate.

1H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) d 1.53-1.73 (m, 8H) 2.14 (m, 1H) 2.24 (m, 1H)2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.80 (d,J=17.9 Hz, 1H) 2.96 (d, J=20.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.2 Hz,1H) 7.15 (d, J=4.7 Hz, 1H) 7.22 (dd, J=8.4, 2.06 Hz, 1H) 7.29 (d, J=1.9Hz, 1H) 8.63 (d, J=4.7 Hz, 1H). MS (APCI) calcd for C₂₅H₂₇ClN₄O₄S;515.03; found M=515.0.

Step 1: Sodium 5-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate

The title compound was prepared by a modification or a reportedprocedure (Shirakawa, K. Yakugaku Zasshi 1960, 80, 1542. A solution of(4-Methyl-pyrimidin-2-yl)-hydrazine (140 g, 1.13 mol), sodium hydroxide(45 g, 1.13 mol) and carbon disulfide (67.7 ml, 1.13 mol) in 50% aqueousethanol (900 ml) was refluxed for 6 hours. The resulting mixture wascooled to ambient temperature and 54.7 g the yellow solid formed wasisolated (54.7 g). It was recrystallized from 50% aqueous ethanol anddried at 40° C./1 Torr for 10 hours to give 44 g (18%) of sodium5-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate, 85% pure byELSD and ¹H NMR.

The initial mother liquid was kept at 0° C. for 2 days. The crystallizedorange solid was isolated by filtration, dried for 10 h at 40° C./1 Torrto give 68.1 g (27%) of the title compound, sodium7-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate. ¹H NMR(DMSO-d₆, 300 MHz) δ, ppm: 2.44 (s, 3H), 6.60 (d, 1H, 7 Hz), 8.29 (d,1H, 7 Hz).

Step 2: 7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol

A solution of sodium5-methyl-1H-[1,2,4]triazolo[4,3-a]pyrimidine-3-thiolate from Step 3 (56g, 0.25 mol) and pyridine (50 ml) in water (169 ml) was heated at refluxfor 60 hours (the reaction was monitored by ¹H NMR). After thedisappearance of starting material the reaction mixture was evaporatedto dryness, dissolved in water (100 ml) and acidified with acetic acid(23 ml). The solid was filtered, washed with water and dried for 4 h at40° C./1 Torr to give 42 g (84%) of desired product, 95% pure by ¹H NMRand ELSD. ¹H NMR (DMSO-d₆, 300 MHz) δ, ppm: 2.68 (s, 3H), 7.34 (d, 1H, 3Hz), 8.56 (d, 1H. 3 Hz).

Example C(96)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 4-methyl-5-(3-pyridyl)-4H-1,2,4-triazole-3-thiol was used in placeof 6-hydroxy-8-mercaptopurine monohydrate.

1H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.52-1.69 (m, 8H) 2.03 (m, 1H) 2.09 (m, 1H)2.36 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.73 (d,J=17.6 Hz, 1H) 2.95 (d, J=17.6 Hz, 1H) 3.71 (s, 3H) 3.80 (s, 3H) 7.01(d, J=8.5 Hz, 1H) 7.18 (dd, J=8.2, 1.9 Hz, 1H) 7.32 (d, J=1.9 Hz, 1H)7.61 (dd, J=7.6, 4.8 Hz, 1H) 8.14 (d, J=8.2 Hz, 1H) 8.74 (d, J=5.00 Hz,1H) 8.91 (s, 1H). MS (APCI) calcd for C₂₇H₂₉ClN₄O₄S: 541.07; foundM=541.1.

Example C(97)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-({5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}thio)-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol, asdescribed in Step 1 of Example C(83), was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.50-1.69 (m, 8H) 2.02 (m, 2H) 2.35 (m, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.72 (d, J=18.1 Hz, 1H)2.87 (s, 6H) 2.92 (d, J=15.0 Hz, 1H) 3.63 (s, 3H) 3.80 (s, 3H) 4.53 (s,2H) 7.01 (d, J=8.5 Hz, 1H) 7.18 (dd, J=8.4, 2.1 Hz, 1H) 7.31 (d, J=1.9Hz, 1H). MS (APCI) calcd for C₂₅H₃₃ClN₄O₄S: 521.08; found M=521.2.

Example C(98)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in placeof 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.52-1.69 (m, 8H) 2.22 (m, 2H) 2.30 (s, 3H)2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.73 (d,J=17.6 Hz, 1H) 2.98 (d, J=17.9 Hz, 1H) 3.81 (s, 3H) 7.06 (d, J=8.2 Hz,1H) 7.24 (dd, J=8.5, 1.9 Hz, 1H) 7.30 (d, J=1.9 Hz, 1H) 8.55 (d, J=1.1Hz, 1H) 8.67 (d, J=2.2 Hz, 1H). MS (APCI) calcd for C₂₅H₂₇C1N₄O₄S:515.03; found M=515.0.

Example C(99)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(4,5-dimethyl-4H-1,2,4-triazol-3-yl)thio]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 4,5-dimethyl-4H-1,2,4-triazole-3-thiol, as shown in Example C(88),Step 1, was used in place of 6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.49-1.64 (m, 8H) 1.92 (m, 2H) 2.33 (m, 1H)2.37 (s, 3H) 2.50 (m, 2H, overlap with dmso) 2.62 (d, J=15 Hz, 1H) 2.80(d, J=17.6 Hz, 1H) 3.55 (s, attenuation due to proximity to H₂O peak)3.80 (s, 3H) 7.02 (d, J=8.5 Hz, 1H) 7.12 (dd, J=8.5, 1.9 Hz, 1H) 7.24(d, J=1.9 Hz, 1H). MS (APCI) calcd for C₂₃H₂₈C1N₃O₄S: 478.01; foundM=478.1.

Example C(100) Methyl5-({6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-4-methyl-4H-1,2,4-triazole-3-carboxylate

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand methyl 5-mercapto-4-methyl-4H-1,2,4-triazole-3-carboxylate, as shownin Example 21, Step 2, was used in place of 6-hydroxy-8-mercaptopurinemonohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.50-1.70 (s, 8H) 1.98 (m, 2H) 2.35 (m, 1H)2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.71 (d, J=18.1 Hz, 1H)2.90 (d, J=17.6 Hz, 1H) 3.81 (s, 3H) 3.81 (s, 3H) 3.88 (s, 3H) 7.02 (d,J=8.2 Hz, 1H) 7.15 (dd, J=8.2, 1.9 Hz, 1H) 7.27 (d, J=10.9 Hz, 1H). MS(APCI) calcd for C₂₄H₂₈ClN₃O₆S: 522.02; found M=522.1.

Example C(101)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(1-methyl-1H-imidazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 2-mercapto-1-methylimidazole was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.86 (m, 2H) 3.72 (s, 3H)3.80 (s, 3H) 7.04 (m, 2H) 7.19 (d, J=1.7 Hz, 1H) 7.46 (s, 1H) 7.58 (s,1H). MS (APCI) calcd for C₂₃H₂₇ClN₂O₄S: 462.99; found 463.1.

Example C(102)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70) where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 4-methyl-4H-1,2,4-triazole-3-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.96 (m, 2H) 2.65 (d, J=15.1Hz, 1H) 2.87 (d, J=17.7 Hz, 1H) 3.16 (s, 1H) 3.64 (s, 3H) 3.80 (s, 3H)7.02 (d, J=8.8 Hz, 1H) 7.16 (dd, J=8.5, 2.20 Hz, 1H) 7.27 (d, J=1.9 Hz,1H) 8.56 (s, 1H). MS (APCI) calcd for C₂₂H₂₆ClN₃O₄S: 463.98; foundM=464.9.

Example C(103)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(1H-imidazol-2-ylthio)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 2-mercaptoimidazole was used in place of 6-hydroxy-8-mercaptopurinemonohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.50-1.64 (m, 8H) 1.89 (m, 2H) 2.71 (d, J=15.0Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.5 Hz, 1H) 7.08 (d, J=5.0 Hz, 1H) 7.21(d, J=1.9 Hz, 1H) 7.46 (s, 2H). MS (APCI) calcd for C₂₂H₂₅C1N₂O₄S:448.97; found M=449.0.

Example C(104)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.53-1.70 (m, 8H) 2.09 (m, 2H, overlap) 2.82(d, J=18.1 Hz, 1H) 3.00 (d, J=18.1 Hz, 1H) 3.78 (s, 3H) 6.97 (d, J=8.5Hz, 1H) 7.13 (dd, J=8.4, 2.1 Hz, 1H) 7.27 (d, J=1.9 Hz, 1H) 7.73 (d,J=5.5 Hz, 2H) 8.71 (d, J=5.8 Hz, 2H). MS (APCI) calcd C₂₆H₂₆ClN₃O₅S:528.03; found M=528.1.

Example C(105)2-({6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-4,6-dimethylnicotinonitrile

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 4,6-dimethyl-2-mercaptonicotinonitrile was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.53-1.71 (m, 8H) 2.01 (s, 3H) 2.06 (m, 2H)2.34 (m, 1H) 2.37 (s, 3H) 2.58 (m, 2H) 2.83 (d, J=17.9 Hz, 1H) 2.93 (d,J=15.0 Hz, 1H) 3.80 (s, attenuation due to proximity to H₂O peak) 6.98(s, 1H) 7.02 (d, J=8.2 Hz, 1H) 7.11 (d, J=5.0 Hz, 1H) 7.23 (d, J=1.9 Hz,1H). MS (APCI) calcd for C₂₇H₂₉ClN₂O₄S: 513.06; found M=513.1.

Example C(106)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(4-phenyl-1,3-thiazol-2-yl)thio]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 2-mercapto-4-phenylthiazole was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.53-1.71 (m, 8H) 2.05 (m, 2H, overlap) 2.35(m, 1H) 2.50 (m, 1H, overlap with dmso) 2.61 (m, 1H) 2.84 (d, J=17.3 Hz,1H) 2.95 (d, J=20.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.5 Hz, 1H) 7.13(dd, J=8.4, 2.1 Hz, 1H) 7.28 (d, J=1.9 Hz, 1H) 7.32 (d, J=7.1 Hz, 1H)7.38 (t, J=7.4 Hz, 2H) 7.85 (d, J=7.7 Hz, 3H).

MS (APCI) calcd for C₂₈H₂₈CINO₄S₂: 542.12; found M=542.0.

Example C(107)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclorpentyl-4-hydroxy-3-[(pyridin-2-ylmethyl)thiol]-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand pyridine-2-methanethiol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

¹H NMR (500 MHz, DMSO-d₆, WET suppression of DMSO-h₆ (2.5 ppm) and H₂O(3.35 ppm) peak areas) δ 1.47-1.58 (m, 8H) 1.80 (m, 2H) 2.23 (m, 1H)2.66 (d, J=20.6 Hz, 1H) 3.80 (s, 3H) 3.96 (m, 2H) 7.03 (d, J=8.2 Hz, 1H)7.07 (d, J=5.0 Hz, 1H) 7.21 (d, J=1.9 Hz, 1H) 7.34 (s, 1H) 7.49 (d,J=7.1 Hz, 1H) 7.84 (s, 1H) 8.44 (s, 1H). MS (APCI) calcd forC₂₅H₂₈ClNO₄S: 474.02; found M=474.1.

Example C(108)6-[2-(3-chloro-4-methoxyphenyl)ethyl]6-cyclopentyl-3-[(2,3-dichlorophenyl)thio]4-hydroxy-5,6-dihydro-2H-pyran-2-one

The title compound was prepared as described in Example C(70), where3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dionewas used in place of3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dioneand 2,3-dichlorothiophenol was used in place of6-hydroxy-8-mercaptopurine monohydrate.

MS (APCI) calcd for C₂₅H₂₅Cl₃O₄S: 527.89; found M=529.0.

Example C(109)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(2-pyridin-2-yl-ethylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example F(7), Step 6,substituting3-chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(0.201 g, 0.52 mmol, described below) in place of3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione,and 2-Pyridin-2-yl-ethanethiol in place of 2-mercaptothiazole. Yield:12.6 mg, 5% yield.

¹HNMR(CDCl₃) δ: 1.48-1.73 (m, 8H), 1.92-1.98 (m, 2H), 2.34 (p, J=8.32Hz, 1H), 2.56-2.62 (m, 4H), 2.80-3.01 (m, 4H), 3.80 (s, 3H), 6.76 (d,J=8.32 Hz, 1H), 6.95 (dd, J1=8.48 Hz, J2=2.08 Hz, 1H), 7.09 (d, J=2.24Hz, 1H), 7.41-7.48 (m, 2H), 7.93 (t, J=7.52 Hz, 1H), 8.52 (d, J=5.12 Hz,1H).

Step 1:2-Chloro-7-(3-chloro-4-methoxy-phenyl)-5-cyclopentyl-5-hydroxy-3-oxo-heptanoicAcid Methyl Ester

Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0°C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil)in THF (30 ml). After 15 min the solution was cooled to −40° C. andn-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resultingdianion was stirred for an additional 30 min and then treated with asolution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one(1.5 g, 5.6 mmol, prepared from Heck route) in THF (10 ml). Afterstirring for 1 h at −40° C., the reaction mixture was quenched withsaturated NH₄Cl and extracted with EtOAc. The organic layers were washedwith brine, dried with Na₂SO₄ and concentrated to an orange oil that wasused without further purification.

Step 2:3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one

A solution of2-Chloro-7-(3-chloro-4-methoxy-phenyl)-5-cyclopentyl-5-hydroxy-3-oxo-heptanoicacid methyl ester (2.33 g, 5.6 mmol, from Step 1 below), andbis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol), dissolved in toluene (18mL) were heated at reflux for 30 mins. The resulting mixture wasconcentrated and purified by silica gel chromatography to give the titlecompound (1.57 g, 75% yield, two Steps).

¹H NMR (CDCl₃): δ 1.36-1.79 (br m, 8H), 2.02 (m, 2H), 2.41 (m, 1H), 2.65(m, 3H), 2.89 (d, 1H, J=17.7 Hz), 3.88 (s, 3H), 6.47 (br s, 1H), 6.85(d, 1H, J=8.4 Hz), 7.01 (dd, 1H, J=8.4, 2.1 Hz), 7.16 (d, 1H, J=2.1 Hz).

Section C: Compounds with Oxygen

Example C(110):2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluorphenyl]-2-methyl-propionitrile

Sodium hydride (60%) (0.49 g, 12.3 mmol) was magnetically stirred in dryTHF (33 mL) and cooled to 0° C. The mixture was then treated with Methylacetoacetate (1.34 mL, 12.3 mmol) dropwise over 15 min. The reaction wasallowed to stir for 30 min at 0° C. To the resulting clear solution wasadded nBuLi (1.6M in Hexanes) (7.71 mL, 12.3 mmol). The reaction wasthen allowed to stir for 30 min at 0° C. To the yellow solution wasadded2-[4-(2-Cyclopentyl-2-oxo-ethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile(1.19 g, 4.1 mmol) as a solution in dry THF (15 mL). The result wasstirred at 0° C. for 15 min and then at room temperature for 90 min. Thesolution was next poured into 0.5N HCl (100 mL) and extracted with EtOAc(2×50 mL). The organics were concentrated and the residue dissolved inMeOH (33 mL) and treated with K₂CO₃ (1.5 g). The mixture was heated to65° C. and maintained for 1 hr. The reaction was cooled and poured into0.5N HCl (100 mL) and extracted with EtOAc (2×50 mL). The organics weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (silica gel) eluting with CH₂Cl₂ through 1% MeOHin CH₂Cl₂ to yield the title compound as a white solid (1.21 g, 79%). ¹HNMR (300 MHz, DMSO-d₆) δ: 1.55 (m, 8H), 1.69 (s, 6H), 2.37 (m, 1H), 2.62(s, 2H), 3.33 (s, 2H), 4.10 (m, 2H), 6.87 (m 2H), 7.34 (m 1H).

Step 4: Preparation of Compound2-[4-(2-Cyclopentyl-2-oxo-ethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile

Potassium carbonate (3.1 g, 22 mmol) was added to a solution of2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol)and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). Themixture was stirred at room temperature for 16 hours. The mixture waspoured into water (100 mL) and extracted with EtOAc (2×50 mL). Theorganics were washed with brine (100 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash columnchromatography (0-15% EtOAc in hexanes) to give the product (1.2 g, 75%yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ: 1.57-1.93 (m, 14H),3.10 (m, 1H), 4.64 (s, 2H), 6.65 (d, J=9.6 Hz, 2H), 7.37 (t, J=8.9 Hz,1H).

Step 3: Preparation of Compound2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile

To a solution of 2-(2-Fluoro-4-methoxy-phenyl)-2-methyl-propionitrile(1.5 g, 7.8 mmol) in CH₂Cl₂ (75 mL) at −78° C. was added Borontribromide (1M solution in CH₂Cl₂) (16 mL, 16 mmol). The solution wasallowed to warm to room temperature and stir for 48 hours. The reactionwas quenched with 0.5N HCl (50 mL) and poured into water (100 mL). Theorganic layer was separated and the aqueous was extracted with CH₂Cl₂(50 mL). The combined organics were washed with water (100 mL), driedover Na₂SO₄, filtered and concentrated. The resulting oil was usedwithout further purification.

Step 2: Preparation of Compound2-(2-Fluoro-4-methoxy-phenyl)-2-methyl-propionitrile

A solution of (2-Fluoro-4-methoxy-phenyl)-acetonitrile (5 g, 30 mmol)and Iodomethane (6.03 mL, 97 mmol) in DMSO (30 mL) was added dropwiseover 2 hours to a stirring solution of KOH (7.47 g, 133 mmol) in water(4 mL) and DMSO (20 mL) at 0° C. The solution was allowed to warm toroom temperature and stirred for 4 hours. The reaction was poured intowater (100 mL) and extracted with EtOAc (2×50 mL). The organics werewashed with water (100 mL) and brine (100 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash columnchromatography (0-10% EtOAc in hexanes) to give the product (4.76 g, 82%yield) as a clear oil.

¹H NMR (300 MHz, CDCl₃) δ: 1.82 (s, 6H), 3.85 (s, 3H), 6.64 (d, J=9.6Hz, 2H), 7.42 (m, 1H).

Step 1: Preparation of Compound (2-Fluoro-4-methoxy-phenyl)-acetonitrile

To a mixture of 1-Bromomethyl-2-fluoro-4-methoxy-benzene (4.5 g, 21mmol) and Tetrabutylammonium iodide (0.66 g, 2.1 mmol) in CH₂Cl₂ (50 mL)was added a solution potassium cyanide (4.0 g, 60 mmol) in water (50mL). The resulting biphasic mixture was stirred vigorously for 8 hours.The reaction was poured into water (100 mL) and extracted with CH₂Cl₂(2×50 mL). The organics were washed with water (100 mL) and brine (100mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash column chromatography (10-30% EtOAc in hexanes) togive the product (2.6 g, 75% yield) as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ: 3.66 (s, 2H), 3.82 (s, 3H), 6.69 (m, 2H), 7.31 (m, 1H).

Example C(111)2-{4-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-ylmethoxy]-2-fluoro-phenyl}-2-methyl-propionitrile

A solution of2-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile(200 mg, 0.54 mmol) in anhydrous MeOH (4.0 mL) was treated with6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (140 mg, 0.86mmol), followed by borane-dimethylamine complex (47 mg, 0.8 mmol) atroom temperature. The reaction was stirred for 5 hours before it wasquenched by the addition of 0.5N HCl (25 mL). The mixture was extractedwith 10% MeOH in CH₂Cl₂ (3×10 mL) and the combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by crystallization from EtOAc/Hexanes to give theproduct as a white solid (91 mg, 32% yield). ¹H NMR (300 MHz, DMSO-d₆)δ: 1.67 (m, 8H), 1.70 (s, 6H), 2.38 (s, 3H), 2.55 (m, 1H), 2.77 (m, 2H),3.77 (m, 2H), 4.12 (m, 1H), 4.44 (m, 1H), 6.97 (m 2H), 7.35 (m, 1H),8.69 (s, 1H), 9.03 (s, 1H), 10.98 (brs, 1H).

Example C(112)2-{4-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-ylmethoxy]-2-fluoro-phenyl}-2-methyl-propionitrile

This compound was prepared analogously to example C (111), except that5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used inplace of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Theresult was a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ: 1.64 (m, 8H),1.70 (s, 6H), 2.50 (1, 1H), 2.57 (s, 3H), 2.63 (s, 3H), 2.79 (m, 2H),3.77 (m, 2H), 4.12 (brs, 1H), 4.50 (m, 1H), 6.95 (m 3H), 7.35 (m, 1H),10.95 (brs, 1H).

Example D(1)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-(methyl-phenyl-amino)-5,6-dihydro-pyran-2-one

To a refluxing solution of N-methylaniline (0.115 mL, 1.1 mmol) andrhodium (II) acetate (9.4 mg) in toluene (1.6 mL) was added6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-diazo-dihydro-pyran-2,4-dione(0.080 g, 0.213 mmol) from Step 1 below over 1 hour. The reaction wasstirred at reflux for three more hours. The reaction was concentrated byrotary evaporation, and then purified by preparatory HPLC to give thedesired product (28 mg, 29% yield).

¹HNMR(CDCl₃) δ: 1.48-1.78 (m, 8H), 1.92-2.07 (m, 2H), 2.38 (p, J=8.10Hz, 1H), 2.51-2.63 (m, 3H), 2.90 (d, J=17.90 Hz, 1H), 3.10 (s, 3H), 3.82(s, 3H), 6.77-6.81 (m, 2H), 6.86 (t, J=7.44 Hz, 1H), 6.94 (dd, J1=8.38Hz, J2=1.98 Hz, 1H), 7.10 (d, J=2.07 Hz), 7.18-7.23 (m, 2H), 7.29 (s,1H).

Step 1:6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-diazo-dihydro-pyran-2,4-dione

To a solution of6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(0.500 g, 1.44 mmol) from Example B(87), and sodium dihydrogen phosphate(0.26 g, 2.16 mmol) in DMF (6 mL) was added 4-acetamidobenzenesulfonylazide (0.52 g, 2.16 mmol). The reaction was stirred for 4 hours, andthen concentrated by rotary evaporation. The crude material was purifiedby flash chromatography to yield the desired compound (0.537 g, 100%yield).

MS (ESI): 373 (M+H).

Example D(2)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-3-phenoxy-5,6-dihydro-pyran-2-one

The target compound was synthesized analogously to Example D(1),substituting phenol (56 mg, 0.598 mmol) in place of N-methylaniline.Yield 12.3 mg, 23% yield.

¹H NMR (CDCl₃) δ: 1.49-1.79 (m, 8H), 1.96-2.18 (m, 2H), 2.46)_(p),J=8.32 Hz, 1H), 2.54 (d, J=17.91 Hz, 1H), 2.63 (t, J=8.32 Hz, 2H), 2.92(d, J=17.59 Hz, 1H), 3.82 (s, 3H), 6.79 (d, J=8.32 Hz, 1H), 6.88 (d,J=8.00 Hz, 2H), 6.95-7.02 (m, 2H), 7.13 (d, J=1.92 Hz, 1H), 7.21-7.29(m, 2H).

Example D(3)6-Cyclopentyl-6{2-[5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-phenyl]-ethyl}-dihydro-pyran-2,4-dione

Methyl acetoacetate (0.36 mL, 3.4 mmol) was added to a cooled −40° C.solution of LDA (prepared from n-BuLi (4.2 ml, 6.71 mmol, 1.6 M inhexanes) and diisoproplyamine (0.94 mL, 6.71 mmol)) in THF (6 mL). Themixture was stirred for 30 mins and then treated with a solution of1-cyclopentyl-3-[5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-phenyl]-propan-1-one(0.39 g, 1.1 mmol) in THF (3 ml). After stirring for 6 h, the reactionmixture was partitioned between 1N HCl and EtOAc. The organic layerswere washed with brine, dried over Na₂SO₄ and concentrated to a yellowoil that was purified by flash column chromatography (10-25% EtOAc inhexanes) to give a clear oil (0.33 g, 65%).

The oil (0.33 g, 0.71 mmol) was dissolved in methanol (5 mL), treatedwith potassium carbonate (0.29 g, 2.1 mmol), and refluxed under N₂ for60 min. The reaction mixture was partitioned between 1N HCl and EtOAc.The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a yellow oil that was purified by silica gelchromatography (20% to 40% EtOAc in hexanes) to give the title compoundas an oil (0.21 g, 69% yield). ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, J=7.6Hz, 3H), 1.51-1.91 (br m, 10H), 2.23 (s, 3H), 2.32 (m, 1H), 2.57 (m,4H), 2.79 (s, 2H), 3.39 (s, 3H), 3.42 (s, 2H), 3.57 (m, 2H), 3.82 (m,2H), 5.25 (s, 2H), 6.83 (s, 1H), 6.91 (s, 1H). C₂₅H₃₆O₆ (M+H)+433.30.

Step 5:1-Cyclopentyl-3-[5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-phenyl]-propan-1-one

A mixture of1-cyclopentyl-3-[5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-phenyl]-propenone(0.75 g, 2.2 mmol) and 5% wt Pd/BaSO₄ (0.15 g) in THF (10 mL) wasstirred under a balloon of H₂ for 30 mins. The reaction mixture wasfiltered through a pad of celite washing with EtOAc. The filtrate wasconcentrated and purified by flash column chromatography (0% to 15%EtOAc in hexanes) to give the title compound as an oil (0.39 g, 52%). ¹HNMR (400 MHz, CDCl₃): δ 1.16 (t, J=7.6 Hz, 3H), 1.54-1.84 (br m, 8H),2.25 (s, 3H), 2.58 (q, J=7.6 Hz, 2H), 2.68 (m, 2H), 2.82 (m, 3H), 3.39(s, 3H), 3.57 (m, 2H), 3.83 (m, 2H), 5.26 (s, 2H), 6.89 (s, 1H), 6.91(s, 1H).

Step 4:1-Cyclopentyl-3-[5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-phenyl]-propenone

Ba(OH)₂ (0.18 g, 1.1 mmol) was added to a solution of5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzaldehyde (0.87 g, 3.5mmol) and 1-cyclopentyl-ethanone (0.59 g, 5.3 mmol) dissolved in EtOH (7mL). The reaction mixture was stirred together for 24 hours and thenpartitioned between 1N HCl and EtOAc. The organic layer was washed withsaturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to an oil.Flash column chromatography (0% to 10% EtOAc in hexanes) gave the titlecompound as a clear oil (0.78 g, 65%). ¹H NMR (400 MHz, CDCl₃): δ 1.20(t, J=7.6 Hz, 3H), 1.54-1.91 (br m, 8H), 2.41 (s, 3H), 2.62 (q, J=7.6Hz, 2H), 3.18 (m, 1H), 3.39 (s, 3H), 3.57 (m, 2H), 3.83 (m, 2H), 5.30(s, 2H), 6.65 (d, J=15.9 Hz, 1H), 6.94 (s, 1H), 7.41 (s, 1H), 7.84 (d,J=15.9 Hz, 1H).

Step 3: 5-Ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzaldehyde

A solution of 5-ethyl-4-hydroxy-2-methyl-benzaldehyde (0.9 g, 5.5 mmol)dissolved in THF (10 mL) was added to a cooled 0° C. suspension of NaH(0.29 g, 7.2 mmol, 60% dispersion in mineral oil) in THF (5 ml). Afterthe addition was complete the reaction mixture was warmed up to roomtemperature and stirred for 30 mins. 2-Methoxyethoxymethyl chloride(0.82 mL, 7.1 mmol) was added and the reaction was stirred for 4 hours.The reaction mixture was quenched with 1N HCl and extracted with EtOAc.The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a yellow oil. Purification by flash columnchromatography (10% to 20% EtOAc in hexanes) gave the title compound asa clear oil (0.89 g, 65%). ¹H NMR (400 MHz, CDCl₃): δ 1.21 (t, J=7.3 Hz,3H), 2.63 (m, 5H), 3.39 (s, 3H), 3.57 (m, 2H), 3.84 (m, 2H), 5.37 (s,2H), 6.95 (s, 1H), 7.62 (s, 1H), 10.15 (s, 1H).

Step 2: 5-Ethyl-4-hydroxy-2-methyl-benzaldehyde

Titanium(IV) chloride (11 mL, 11 mmol, 1M in CH₂Cl₂) followed bydichloromethyl methyl ether (1.04 g, 9.1 mmol) was added to a cooled 0°C. solution of 2-ethyl-5-methyl-phenol (0.75 g, 5.5 mmol) The reactionmixture was stirred for 30 mins and then warmed up to rt and stirred foranother 30 mins. The mixture was poured into ice and extracted withEtOAc. The organic layers were washed with satd NaHCO₃, brine, driedover Na₂SO₄ and concentrated to a purple oil. Purification by flashcolumn chromatography (0% to 10% EtOAc in hexanes) gave the titlecompound as an oil (0.45 g, 50%). ¹H NMR (400 MHz, CDCl₃): δ 1.26 (t,J=7.6 Hz, 3H), 2.60 (s, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.37 (s, 1H), 6.62(s, 1H), 7.62 (s, 1H), 10.11 (s, 1H).

Step 1: 2-Ethyl-5-methyl-phenol

A mixture of 1-(2-hydroxy-4-methyl-phenyl)-ethanone (5 g, 33.3 mmol) and10 wt % Pd/C (2 g, Degussa type) in MeOH (50 mL) was stirred under aballoon of H₂ for 24 hours. The reaction mixture was filtered through apad of celite washing with EtOAc. The filtrate was concentrated to aclear oil (4.5 g, 99%). ¹H NMR (400 MHz, CDCl₃): δ 1.23 (t, J=7.6 Hz,3H), 2.27 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 4.68 (s, 1H), 6.59 (s, 1H),6.71 (d, J=7.7 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H).

Example D(4)6-Cyclopentyl-6-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one

The title compound was prepared analogously to Example A(123) where6-cyclopentyl-6-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-dihydro-pyran-2,4-dione(Example D(5)) was substituted in place of6-cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione.¹H NMR (400 MHz, DMSO-d₆): δ 1.39-1.69 (br m, 8H), 2.05-2.11 (m, 2H),2.39 (m, 1H), 2.49-2.55 (m, 9H), 2.75 (d, J=17.6 Hz, 1H), 3.11 (t, J=8.8Hz, 2H), 3.70 (d, J=16.2 Hz, 1H), 3.82 (d, J=16.2 Hz, 1H), 4.48 (t,J=8.8 Hz, 2H), 6.62 (d, J=8.1 Hz, 1H), 6.92 (d, J=6.6 Hz, 1H), 7.04 (s,1H), 7.07 (s, 1H). Anal. Calcd. For C₂₈H₃₂N₄O₄.0.4H₂O: C, 67.83; H,6.67; N 11.30. Found: C, 67.86; H, 6.74; N, 11.40.

Example D(5)6-Cyclopentyl-6-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example D(1) where2,3-dihydro-benzofuran-5-carbaldehyde was substituted in place of5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzaldehyde in step 4 ofthat example. ¹H NMR (400 MHz, CDCl₃) δ: 1.51-180 (br m, 8H), 1.76-2.01(m, 2H), 2.28 (m, 1H), 2.60 (t, J=8.6 Hz, 2H), 2.76 (s, 2H), 3.17 (t,J=8.6 Hz, 2H), 3.42 (s, 2H), 4.55 (t, J=8.8 Hz, 2H), 6.70 (d, J=8.1 Hz,1H), 6.87 (d, J=9.6 Hz, 1H), 6.97 (s, 1H). Anal. Calcd. For C₂₀H₂₄O₄: C,73.15; H, 7.37. Found: C, 72.88; H, 7.35.

Example D(6)6-Cyclopentyl-6-{2-[5-ethyl-2-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example D(1) where1-(4-fluoro-2-hydroxy-phenyl)-ethanone was substituted in place of1-(2-hydroxy-4-methyl-phenyl)-ethanone in step 1 of that example. ¹H NMR(400 MHz, CDCl₃): δ 1.15 (t, J=7.6 Hz, 3H), 1.44-1.96 (br m, 10H), 2.31(m, 1H), 2.53-2.67 (m, 4H), 2.77 (s, 2H), 3.39 (s, 3H), 3.43 (s, 2H),3.56 (m, 2H), 3.81 (m, 2H), 5.24 (s, 2H), 6.06 (m, 2H).

Example D(7)6-Cyclopentyl-6-{2-[5-ethyl-2-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example D(1) where5-ethyl-2-(2-methoxy-ethoxymethoxy)-benzaldehyde (from step 1 below) wassubstituted in place of5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzaldehyde in step 4 ofthat example. ¹H NMR (400 MHz, CDCl₃): δ 1.15 (t, J=7.6 Hz, 3H),1.44-1.98 (br m, 10H), 2.35 (m, 1H), 2.56 (q, J=7.6 Hz, 2H), 2.56-2.70(m, 2H), 2.74 (d, J=16.2 Hz, 1H), 2.56 (d, J=16.2 Hz, 1H), 3.38 (s, 3H),3.43 (s, 2H), 3.56 (m, 2H), 3.80 (m, 2H), 5.25 (s, 2H), 6.91 (d, J=2.1Hz, 1H), 6.99 (dd, J=8.4, 2.1 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H).

Step 1: 5-Ethyl-2-(2-methoxy-ethoxymethoxy)-benzaldehyde

CHCl₃ (10 mL) was slowly added to a suspension of 4-ethyl phenol (30 g,0.25 mol) in 10N NaOH (150 mL). After the vigorous reaction died down,the mixture was stirred for 20 mins and then additional CHCl₃ (20 mL)was added very slowly. The reaction was cooled to 0° C. and let standfor 2 hrs. The reaction mixture was acidified with 12 N HCl, dilutedwith water and then extracted with CH₂Cl₂ The organics were concentratedto a brown oil (17.3 g).

The oil was dissolved in THF (50 mL) and added to a cooled 0° C.suspension of NaH (5.76 g, 0.14 mol, 60% dispersion in mineral oil) inTHF (100 ml). After the addition was complete the reaction mixture waswarmed up to room temperature and stirred for 1 hr. Methoxyethoxymethylchloride (17.1 mL, 0.15 mmol) was added and the reaction was stirred for20 hours. The reaction mixture was quenched with 1N HCl and extractedwith EtOAc. The organic layers were washed with 1N NaOH, brine, driedover Na₂SO₄ and concentrated to a brown oil. Purification by flashcolumn chromatography (0% to 10% EtOAc in hexanes) gave the titlecompound as a yellow oil (10.8 g, 18%). ¹H NMR (400 MHz, CDCl₃): δ 1.22(t, J=7.6 Hz, 3H), 2.63 (q, J=7.6 Hz, 2H), 3.38 (s, 3H), 3.57 (m, 2H),3.87 (m, 2H), 5.38 (s, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.3, 2.3Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 10.47 (s, 1H).

Example D(8)6-[2-(2-Benzyloxy-5-ethyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione

The title compound was prepared analogously to Example D(1) where2-benzyloxy-5-ethyl-benzaldehyde (from step 2 below) was substituted inplace of 5-ethyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzaldehyde instep 4 of that example. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.8 Hz,3H), 1.33-1.70 (br m, 8H), 1.87 (m, 1H), 1.99 (m, 1H), 2.27 (m, 1H),2.54-2.74 (m, 6H), 3.27 (s, 2H), 5.01 (s, 2H), 6.83 (d, J=8.1 Hz, 1H),6.93 (s, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.34-7.40 (m, 5H). MS (ESI):421.10 (M+H⁺).

Step 2: 2-Benzyloxy-5-ethyl-benzaldehyde

n-BuLi (7.56 mL, 18.9 mmol, 2.5M in hexanes) followed by DMF (5.5 mL)were added to a cooled −78° C. solution of1-benzyloxy-2-bromo-4-ethyl-benzene (5 g, 17.2 mmol) in THF (40 mL). Thereaction was stirred at −78° C. for 1 hr and then warmed up to rt. After2 hrs the reaction was quenched with 1N HCl and extracted with EtOAc.The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to a yellow oil. Purification by flash columnchromatography (0% to 5% EtOAc in hexanes) gave the title compound as aclear oil (3.6 g, 87%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (t, J=7.8 Hz,3H), 2.62 (q, J=7.8 Hz, 2H), 5.17 (s, 2H), 6.97 (d, J=8.6 Hz, 1H),7.33-7.45 (m, 6H), 7.69 (s, 1H), 10.54 (s, 1H).

Step 1: 1-Benzyloxy-2-bromo-4-ethyl-benzene

Potassium carbonate (21.6 g, 0.16 mol) followed by benzyl bromide (6.2mL, 52 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.6 g,7.9 mmol, from step 1 of Example B(98)) in DMF (75 mL). The mixture wasstirred for 20 hours and then partitioned between 1N HCl and EtOAc. Theorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The crude yellow oil was purified by flash columnchromatography (hexanes) to give the desired product (13.1 g, 87%). ¹HNMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.6 Hz, 3H), 2.56 (q, J=7.8 Hz, 2H),5.13 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.04 (dd, J=8.3, 2.3 Hz, 1H), 7.32(m, 1H), 7.38 (m, 3H), 7.47 (d, J=7.9 Hz, 2H).

Example E(1)3-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylethynyl)-phenyl]-3-oxo-propionitrile

The title compound was prepared analogously to example A(75), where thehydrogenation of the triple bond Step was omitted. Yield 48 mg, 32%.

¹H NMR (CDCl₃): δ 1.35 to 1.71 (bm, 8H), 2.34 (m, 1H), 2.66 (d, J=17.8Hz, 1H), 2.87 (d, J=17.4 Hz, 1H), 3.36 (d, J=20.2 Hz, 1H), 3.75 (d,J=19.8 Hz, 1H), 3.93 (s, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.6 Hz,2H). ESIMS (M+Na⁺): 372.13.

Example E(2)3-[5-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylethynyl)-thiophen-2-yl]-3-oxo-propionitrile

The title compound was prepared analogously to Example A(86), , where3-(5-Bromo-thiophen-2-yl)-isoxazole was substituted in place of.1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example, and the hydrogenation of the triple bond Step was omitted(Note that the isoxazole opens to the cyanomethyl ketone during theSonogashira coupling Step). Yield 30 mg, 35%.

¹H NMR (CDCl₃): δ 1.35 to 1.68 (bm, 8H), 2.33 (m, 1H), 2.65 (d, J=17.7Hz, 1H), 2.87 (d, J=17.4 Hz, 1H), 3.37 (d, J=20.2 Hz, 1H), 3.70 (d,J=20.0 Hz, 1H), 3.83 (s, 2H), 7.52 (m, 2H). ESIMS (M+Na⁺): 378.09.

Example E(3)[3-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-ylethynyl)-phenyl]-acetonitrile

The title compound was prepared analogously to example A(86), , where(3-Bromo-phenyl)-acetonitrile was substituted in place of.1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid methyl ester in Step 3 ofthat example, and the hydrogenation of the triple bond Step was omitted.

¹H NMR (CDCl₃): δ 1.44 to 1.72 (bm, 8H), 2.82 (m, 1H), 3.79 (d, J=17.4Hz, 1H), 2.87 (d, J=17.4 Hz, 1H), 3.35 (d, J=20.0 Hz, 1H), 3.61 (s, 2H),3.81 (d, J=20.2 Hz, 1H), 7.13 (s, 1H), 7.24 (bm, 4H). ESIMS (M+Na⁺):344.14.

Example F(1)6-Cyclopentyl-6-[4-(4-hydroxy-2,6-dimethyl-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione

To5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester (60 mg, 0.155 mmol) from Step 2 below was added NaOH(0.3 M in MeOH, 1 mL, 0.31 mmol). The solution was stirred overnight,and then quenched with 1 N HCl (5 mL). The solution was extracted with4×10 mL CH₂Cl₂. The organic layer was dried over Na₂SO₄, and then thesolids were removed by filtration. After concentrating the motherliquor, the resulting oil was purified by flash chromatography to yieldthe desired product (54 mg, 98% yield).

¹H NMR (CDCl₃) δ: 1.35-1.75 (m, 8H), 1.93-1.99 (m, 3H), 2.10 (s, 3H),2.23 (s, 3H), 2.51 (t, J=7.33 Hz, 2H), 2.69 (d, J=16.17 Hz, 1H), 2.83(d, J=16.18 Hz, 1H), 3.37 (s, 2H), 4.66 (s, 1H), 6.52 (s, 1H), 7.05 (s,1H). MS (ESI): 353 (M−H).

Step 1: 1-Cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one

A solution of 1-cyclopentyl-pent-4-yn-1-one (0.33 g, 2.2 mmol) fromexample F(7), Step 2,4-iodo-2,5-dimethyl-phenol (0.54 g, 2.2 mmol),copper (I) iodide (33 mg, 0.18 mmol),trans-dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol),and diisopropylamine (2.2 mL) in DMF (2.2 mL) was heated to 100° C. for30 minutes. The reaction was cooled to room temperature and diluted with10 mL of EtOAc. The resulting slurry was filtered, and the mother liquorwas concentrated to a black oil. The oil was then purified by flashchromatography to give the desired product (112 mg, 19% yield).

¹H NMR (CDCl₃) δ: 1.58-1.84 (m, 8H), 2.15 (s, 3H), 2.29 (s, 3H),2.68-2.70 (m, 2H), 2.75-2.79 (m, 2H), 2.90 (p, J=8.08 Hz, 1H), 6.57 (s,1H), 7.10 (s, 1H).

Step 2:5-Cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicAcid Methyl Ester

To a freshly prepared solution of LDA (1 M, 2.2 mL, 2.2 mmol) cooled to0° C. was added methyl acetoacetate (0.12 mL, 1.1 mmol) dissolved in THF(1 mL). After stirring for 30 minutes,1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one (0.10 g,0.37 mmol) from Step 1 above dissolved in THF (1 mL) was added. Thereaction was stirred for 1 hour, and then warmed to room temperature.After quenching with 10 mL saturated ammonium chloride, the layers wereseparated. The aqueous layer was extracted with 2×15 mL CH₂Cl₂, and theorganic layers were combined. After drying over Na₂SO₄, and filtering toremove the solids, the mother liquor was concentrated to an oil. Flashchromatography of the oil gave the desired product (69 mg, 48% yield).

MS (ESI): 385 (M−H).

Example F(2)3-[4-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-but-1-ynyl]-benzenesulfonamide

The desired product was prepared analogously to example F(1),substituting5-cyclopentyl-5-hydroxy-3-oxo-9-(3-sulfamoyl-phenyl)-non-8-ynoic acidmethyl ester (80 mg, 0.19 mmol) from Step 2 below in place of5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester. Yield: 17 mg, 23%.

¹H NMR (CDCl₃) δ: 1.43-1.74 (m, 8H), 1.93-2.05 (m, 2H), 2.20 (p, J=8.59Hz, 1H), 2.52 (t, J=7.45 Hz, 2H), 2.70 (d, J=16.17 Hz, 1H), 2.80 (d,J=16.17 Hz, 1H), 3.39 (s, 2H), 4.82 (s, 2H), 7.38 (t, J=7.83 Hz, 1H),7.50 (d, J=8.84 Hz, 1H), 7.76 (d, J=7.83 Hz, 1H), 7.90 (t, J=1.52 Hz,1H). MS (ESI): 388 (M-H).

Step 1: 3-(5-Cyclopentyl-5-oxo-pent-1-ynyl)-benzenesulfonamide

The desired product was prepared analogously to example F(1), Step 1substituting 3-bromo-benzenesulfonamide (400 mg, 2.7 mmol) in place of4-iodo-2,5-dimethyl-phenol. Yield: 0.556 g, 67%.

¹H NMR (CDCl₃) δ: 1.66-1.96 (m, 8H), 2.77 (t, J=6.82 Hz, 2H), 2.88 (t,J=6.82 Hz, 2H), 2.99 (p, J=7.96 Hz, 1H), 5.01 (s, 1H), 5.09 (s, 1H),7.52 (t, J=7.83 Hz, 1H), 7.79-7.82 (m, 1H), 7.94-7.97 (m, 1H), 8.17 (t,J=1.89 Hz, 1H).

Step 2: 5-Cyclopentyl-5-hydroxy-3-oxo-9-(3-sulfamoyl-phenyl)-non-8-ynoicAcid Methyl Ester

The desired product was prepared analogously to example A(86), Step 2,substituting 3-(5-cyclopentyl-5-oxo-pent-1-ynyl)-benzenesulfonamide (200mg, 0.66 mmol) from Step 1 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one. Yield:89 mg, 32%.

MS (ESI): 420 (M−H).

Example F(3)6-Cyclopentyl-6-[4-(2-methylsulfanyl-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione

The desired product was prepared analogously to example F(1),substituting5-cyclopentyl-5-hydroxy-9-(2-methylsulfanyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester (43 mg, 0.11 mmol) from Step 2 below in place of5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester. Yield: 38 mg, 97%.

¹H NMR (CDCl₃) δ: 1.41-1.69 (m, 8H), 1.94-2.01 (m, 2H), 2.13-2.18 (m,1H), 2.36 (s, 3H), 2.55 (t, J=7.45 Hz, 2H), 2.67 (d, J=16.17 Hz, 1H),2.87 (d, J=16.17 Hz, 1H), 3.34 (d, J=8.84 Hz, 2H), 6.93-7.01 (m, 2H),7.14-7.16 (m, 1H), 7.24 (d, J=6.32 Hz, 1H). MS (ESI): 355 (M-H).

Step 1: 1-Cyclopentyl-5-(2-methylsulfanyl-phenyl)-pent-4-yn-1-one

The desired product was prepared analogously to example F(1), Step 1,substituting 2-bromothioanisole (0.58 g, 2.8 mmol) in place of4-iodo-2,5-dimethyl-phenol. Yield: 63 mg, 8.3%.

MS (APCI): 273 (M+H).

Step 2:5-Cyclopentyl-5-hydroxy-9-(2-methylsulfanyl-phenyl)-3-oxo-non-8-ynoicAcid

The desired product was prepared analogously to example F(1), Step 2,substituting 1-Cyclopentyl-5-(2-methylsulfanyl-phenyl)-pent-4-yn-1-one(60 mg, 0.22 mmol) from Step 1 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one. Yield:43 mg, 50%.

MS (ESI): 387 (M−H).

Example F(4)6-Cyclopentyl-6-[4-(2-trifluoromethoxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione

The desired product was prepared analogously to example F(1),substituting5-cyclopentyl-5-hydroxy-3-oxo-9-(2-trifluoromethoxy-phenyl)-non-8-ynoicacid methyl ester (72 mg, 0.17 mmol) from Step 2 below in place of5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester. Yield: 25 mg, 37%.

¹H NMR (CDCl₃) δ: 1.33-1.73 (m, 8H), 1.89-2.06 (m, 2H), 2.14-2.23 (m,1H), 2.55 (t, J=7.58 Hz, 2H), 2.69 (d, J=16.17 Hz, 1H), 2.84 (d, J=16.17Hz, 1H), 3.37 (s, 2H), 7.15-7.21 (m, 2H), 7.23-7.27 (m, 1H), 7.38-7.44(m, 1H). MS (ESI): 393 (M−H).

Step 1: 1-cyclopentyl-5-(2-trifluoromethoxy-phenyl)-pent-4-yn-1-one

The desired product was prepared analogously to example F(1), Step 1,substituting 1-Iodo-2-trifluoromethoxy-benzene (0.80 g, 2.8 mmol) inplace of 4-iodo-2,5-dimethyl-phenol. Yield: 0.247 g, 28%.

¹H NMR (CDCl₃) δ: 1.80-2.05 (m, 8H), 2.70-3.12 (m, 5H), 7.40-7.45 (m,2H), 7.49-7.53 (m, 1H), 7.64-7.69 (m, 1H).

Step 2:5-cyclopentyl-5-hydroxy-3-oxo-9-(2-trifluoromethoxy-phenyl)-non-8-ynoicAcid Methyl Ester

The desired product was prepared analogously to example F(1), Step 2,substituting 1-cyclopentyl-5-(2-trifluoromethoxy-phenyl)-pent-4-yn-1-one(200 mg, 0.65 mmol) from Step 1 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one. Yield:72 mg, 26%.

MS (ESI): 425 (M−H).

Example F(5)6-Cyclopentyl-6-[4-(4-fluoro-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione

The desired product was prepared analogously to example F(1),substituting5-cyclopentyl-9-(4-fluoro-phenyl)-5-hydroxy-3-oxo-non-8-ynoic acidmethyl ester (400 mg, 1.1 mmol) from Step 2 below in place of5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester. Yield: 190 mg, 53%. MS (ESI): 327 (M−H).

Step 1: 1-Cyclopentyl-5-(4-fluoro-phenyl)-pent-4-yn-1-one

The desired product was prepared analogously to example F(1), Step 1,substituting 1-fluoro-4-iodo-benzene (0.38 mL, 3.3 mmol) in place of4-iodo-2,5-dimethyl-phenol. Yield: 0.415 g, 51%.

¹H NMR (CDCl₃) δ: 1.44-1.74 (m, 8H), 2.52-2.58 (m, 2H), 2.66 (t, J=6.95Hz, 2H), 2.79 (p, J=7.96 Hz, 1H), 6.85 (t, J=8.84 Hz, 2H), 7.22 (ddd,J1=11.81 Hz, J2=5.24 Hz, J3=2.65 Hz, 2H).

Step 2: 5-Cyclopentyl-9-(4-fluoro-phenyl)-5-hydroxy-3-oxo-non-8-ynoicAcid Methyl Ester

The desired product was prepared analogously to example F(1), Step 2,substituting 1-cyclopentyl-5-(4-fluoro-phenyl)-pent-4-yn-1-one (300 mg,1.23 mmol) from Step 1 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one. Thecrude product was used directly without purification.

MS (ESI): 359 (M−H).

Example F(6)6-Cyclopentyl-6-(4-p-tolyl-but-3-ynyl)-dihydro-pyran-2,4-dione

The desired product was prepared analogously to example F(1),substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-p-tolyl-non-8-ynoic acidmethyl ester (400 mg, 1.1 mmol) from Step 2 below in place of5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoicacid methyl ester. Yield: 180 mg, 50%.

MS (ESI): 323 (M−H).

Step 1: 1-Cyclopentyl-5-p-tolyl-pent-4-yn-1-one

The desired product was prepared analogously to example F(1), Step 1,substituting 4-iodotoluene (0.727 g, 3.3 mmol) in place of4-iodo-2,5-dimethyl-phenol. Yield: 0.412 g, 52%.

¹H NMR (CDCl₃) δ: 1.49-1.79 (m, 8H), 2.26 (s, 3H), 2.57-2.61 (m, 2H),2.69-2.73 (m, 2H), 2.84{(p, J=8.08 Hz, 1H), 7.01 (d, J=7.83 Hz, 2H),7.19 (d, J=8.34 Hz, 2H).

Step 2: 5-Cyclopentyl-5-hydroxy-3-oxo-9-p-tolyl-non-8-ynoic Acid MethylEster

The desired product was prepared analogously to example F(1), Step 2,above substituting 1-cyclopentyl-5-p-tolyl-pent-4-yn-1-one (300 mg, 1.23mmol) from Step 1 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one. Thecrude product was used directly without purification.

MS (ESI): 355 (M−H).

Example F(7)6-Cyclopentyl-4-hydroxy-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-3-(thiazol-2-ylsulfanyl)-5,6-dihydro-pyran-2-one

To a solution of3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione(216 mg, 0.6 mmol) from Step 5 below and 2-mercaptothiazole (141 mg, 1.2mmol) in DMF (6 mL) was added triethylamine (0.15 mL, 1.2 mmol). Thereaction was stirred at 50° C. for 2.5 hours and then quenched with 10mL of saturated ammonium chloride. The mixture was further acidified toa pH of 1-2 with 1 N HCl. To this mixture was added 10 mL CH₂Cl₂ and thelayers were separated. The aqueous was extracted with 2×10 mL CH₂Cl₂,and the organic layers were combined. After drying the organic layerover MgSO₄, the solids were filtered away and the liquid wasconcentrated to an oil. The oil was chromatographed on silica to yieldthe desired product (28 mg, 11% yield).

¹H NMR (CDCl₃) δ: 1.09-1.58 (m, 8H), 1.93-2.05 (m, 3H), 2.58-2.82 (m,4H), 6.59 (d, J=6.82 Hz, 2H), 6.65 (d, J=7.58 Hz, 1H), 6.96-7.00 (m,1H), 7.32 (d, J=3.28 Hz, 1H), 7.46 (d, J=3.28 Hz, 1H). MS (ESI): 440(M−H).

Step 1: Pent-4-ynethioic acid S-pyridin-2-yl Ester

To a solution of 4-pentynoic acid (9.27 g, 94.5 mmol) dissolved inCH₂Cl₂ (125 mL) was added triphenylphosphine (32.2 g, 123 mmol) and2,2′-dithiodipyridine (26 g, 118 mmol) and stirred at room temperaturefor 2 hours. The reaction was concentrated by rotary evaporation, andthen chromatographed to yield the desired product (17.9 g, 99% yield).

MS (ESI): 192 (M+H).

Step 2: 1-cyclopentyl-pent-4-yn-1-one

To a solution of pent-4-ynethioic acid S-pyridin-2-yl ester (17.9 g, 94mmol), dissolved in THF (900 mL) cooled to −78° C. was addedcyclopentylmagnesium bromide (2.0 M, 94 mL, 188.5 mmol). The reactionwas stirred for 15 minutes, and then warmed to −50° C. The reaction waspoured into 500 mL 1 N HCl and the layers were separated. The aqueouslayer was extracted with 2×200 mL diethyl ether and the organic layerswere combined. The organics were then washed with 300 mL of 1 N NaOH.The organic layer was dried over Mg SO₄, and the solids were removed byfiltration. The solvent was removed by rotary evaporation to give thedesired compound (14.0 g, 99% yield).

¹H NMR (CDCl₃) δ: 1.54-1.87 (m, 8H), 1.94 (t, J=2.65 Hz, 1H), 2.45 (dt,J1=7.33 Hz, J2=2.78 Hz, 2H), 2.71 (t, J=7.58 Hz, 2H), 2.87 (p, J=7.96Hz, 1H).

Step 3: 2-Chloro-5-cyclopentyl-5-hydroxy-3-oxo-non-8-ynoic Acid MethylEster

A slurry of NaH (3.2 g, 60% suspension in mineral oil, 80 mmol) in dryTHF (250 mL) was cooled to −40° C. Methyl-2-chloroacetoacetate (9.74 mL,80 mmol) was added slowly. The reaction was stirred until all gasevolution had ceased, and then butyl lithium (2.5 M, 32 mL, 80 mmol) wasadded. The reaction was stirred for 10 minutes, and then1-cyclopentyl-pent-4-yn-1-one (4.0 g, 27 mmol) from Step 2 above, wasadded as a solution in 20 mL THF. The reaction was stirred 1 hour, andthen warmed to room temperature. The reaction was quenched with 1 N HCl(200 mL) and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ and the organic layers were combined. The organic layer waswashed with water, and then concentrated by rotary evaporation. Thecrude product was purified by chromatography to yield the pure product(6.345 g, 78% yield).

MS (ESI): 298 (M−H), 300 (M+2−H).

Step 4: 6-But-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione

A slurry of 2-chloro-5-cyclopentyl-5-hydroxy-3-oxo-non-8-ynoic acidmethyl ester (6.0 g, 20 mmol) from Step 3 above and K₂CO₃ (11 g, 80mmol) in methanol (100 mL) was stirred at 50° C. for 1.5 hours. Thereaction was concentrated by rotary evaporation, and then re-dissolvedin ethyl acetate. The solution was washed with water, and then saturatedNa₂CO₃. The organic layer was dried over sodium sulfate. After removingthe solids by filtration, the organic layer was concentrated by rotaryevaporation to yield the desired product (5.24 g, 97% yield).

MS (ESI): 267 (M−H), 269 (M+2−H).

Step 5:3-Chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione

A solution of6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (200 mg,0.66 mmol) from Step 4 above, 3-iodophenol (145 mg, 0.66 mmol),bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.026 mmol),and copper (I) iodide (10 mg, 0.052 mmol) in DMF (0.66 mL) anddiisopropylamine (0.66 mL) was sonicated for 1 minute and then heated to90° C. for 20 minutes. The reaction was cooled to room temperature, andthen diluted with 10 mL CH₂Cl₂. The reaction was then neutralized to apH of 4 with 6 N HCl and the layers were separated. The aqueous layerwas extracted with 3×10 mL CH₂Cl₂ and the organic layers were combined,and then dried over sodium sulfate. After filtering the solids, theorganic layer was concentrated to a dark oil, which was used withoutfurther purification.

MS (ESI): 359 (M−H), 361 (M+2−H).

Example G(1)6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-(pyridin-3-ylmethoxy)-5,6-dihydro-2H-pyran-2-one

The title compound was prepared analogously to Example B(78), where3-(chloromethyl)pyridine hydrochloride was substituted in place ofbenzyl bromide in that example.

¹H NMR (CDCl₃): δ 1.41-1.70 (bm, 8H), 2.02 (m, 3H), 2.44 (m, 2H), 2.63(m, 2H), 3.87 (s, 3H), 4.96 (s, 2H), 5.30 (s, 1H), 6.83 (d, J=8.64 Hz,1H), 7.02 (d, J=8.64 Hz, 1H), 7.17 (s, 1H), 7.36 (t, J=4.80 Hz, 1H),7.72 (d, J=7.68 Hz, 1H), 8.65 (s, 2H).

Example G(2)6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-(pyridin-2-ylmethoxy)-5,6-dihydro-pyran-2-one

The target compound was isolated out of the same reaction that was usedfor Example B(81).

¹H NMR (CDCl₃)?: 1.57-1.80 (m, 8H), 1.89-20.4 (m, 2H), 2.39-2.50 (m,2H), 2.60-2.66 (m, 2H), 2.74-2.80 (d, J=17.27 Hz, 1H), 3.87 (s, 3H),5.28 (s, 1H), 6.84 (d, J=8.32 Hz, 1H), 6.99-7.03 (m, 1H), 7.24-7.30 (m,1H), 7.38 (d, J=8.00 Hz, 1H), 7.74 (tt, J1=7.26 Hz, J2=7.26 Hz, J3=1.76Hz, 1H), 8.61 (d, J=3.84 Hz, 1H).

Example G(3):6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-methoxy-5,6-dihydro-pyran-2-one

To a solution of6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione(60 mg, 0.17 mmol) from Example B(87), dissolved in DMF (1.5 mL), wereadded DBU (0.028 mL, 0.188 mmol) and iodomethane (0.011 mL, 0.17 mmol).The reaction was stirred at room temperature overnight, and then wasquenched with water. The reaction was extracted with EtOAc, and theorganic layers were combined. After washing with saturated NaCl, theorganic layer was dried over Na₂SO₄. The solids were removed byfiltration, and the liquid was concentrated by rotary evaporation.Purification by preparatory HPLC gave the desired product (8.2 mg, 13%yield).

¹H NMR (CDCl₃) δ: 1.47-1.69 (m, 8H), 1.89-1.95 (m, 2H), 2.25-2.35 (m,2H), 2.52-2.63 (m, 3H), 3.67 (s, 3H), 3.80 (s, 3H), 6.77 (d, J=8.32 Hz,1H), 6.94 (dd, J1=8.32 Hz, J2=2.24 Hz, 1H), 7.09 (d, J=1.92 Hz, 1H).

Example H(1)N-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-3-furan-2-yl-propionamide

A solution of 6-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione(90 mg, 0.4 mmol) from Step 5 below, TEA (0.22 mL, 1.6 mmol),3-furan-2-yl-propionic acid (67 mg, 0.48 mmol) and HATU (182 mg, 0.48mmol) in DMF (2 mL) was stirred at room temperature overnight. Thereaction was purified directly by preparatory HPLC to yield the desiredproduct (26 mg, 19% yield).

¹H NMR (CDCl₃) δ: 1.27-3.47 (m, 21H), 6.94 (s, 1H), 6.19 (s, 1H), 7.22(s, 1H). MS (ESI): 346 (M−H).

Step 1: (3-Chloro-1-cyclopentyl-propan-1-one

A solution of cyclopentanecarbonyl chloride (10 g, 75 mmol) and AlCl₃(11.1 g, 83 mmol) in CH₂Cl₂ (100 mL) was cooled to −10° C. A solution ofvinyltrimethylsilane (12 mL, 75 mmol) in CH₂Cl₂ (50 mL) was added dropwise over 30 minutes. The reaction was stirred for 20 additionalminutes, and then poured over 200 g of ice. The layers were separated,and the aqueous layer was extracted with CH₂Cl₂. The organic layers werecombined and washed with saturated NaHCO₃. The organic was then driedover Na₂SO₄, the solids were filtered away, and the product was purifiedby distillation (7.17 g, 60%).

¹H NMR (CDCl₃) δ: 1.43-1.70 (m, 8H), 2.69-2.80 (m, 3H), 3.61 (t, J=6.57Hz, 2H).

Step 2: (3-Cyclopentyl-3-oxo-propyl)-carbamic Acid Tert-Butyl Ester

To a solution of 3-chloro-1-cyclopentyl-propan-1-one (2.913 g, 18.1mmol) from Step 1 above in DMF (40 mL) was added sodium azide (1.77 g,27.2 mmol). The reaction was heated to 70° C. for 3 hours. The reactionwas cooled to room temperature, and then diluted with 100 mL of ethylacetate and 100 mL of water. The layers were separated, and the aqueouswas extracted with 2×50 mL of ethyl acetate. The organic layer was thenwashed with 2×50 mL of water. The organic layer was dried over sodiumsulfate, filtered, and concentrated to an oil. The oil was thendissolved in ethanol (75 mL) and TFA was added (3 mL). To this solutionwas added 10% Pd/C (300 mg). The slurry was stirred under a hydrogenatmosphere for 2 hours. The solids were removed by filtration, and theorganic was concentrated by rotary evaporation to a black oil. The blackoil was dissolved in THF (100 mL) and TEA (7.5 mL) and di-tert-butylpyrocarbonate (1 M in THF, 40 mL, 40 mmol) were added. The reaction wasstirred at room temperature for 18 hours, and then concentrated byrotary evaporation. The crude oil was purified by flash chromatographyto yield the product (1.677 g, 38%).

¹H NMR (CDCl₃) δ: 1.43 (s, 9H), 1.56-1.84 (m, 8H), 2.68 (t, J=5.65 Hz,2H), 2.85 (p, J=5.65 Hz, 1H), 3.36 (q, J=6.03, 2H).

Step 3:7-tert-Butoxycarbonylamino-5-cyclopentyl-5-hydroxy-3-oxo-heptanoic AcidMethyl Ester

The desired product was prepared analogously to example F(1), Step 2replacing1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one, fromStep 2 above with (3-cyclopentyl-3-oxo-propyl)-carbamic acid tert-butylester (1,6 g, 6.6 mmol) described in Step 2 above. Yield: 1.36 g, 58%.

MS (ESI): 356 (M−H).

Step 4:[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-carbamic AcidTert-Butyl Ester

To 7-tert-butoxycarbonylamino-5-cyclopentyl-5-hydroxy-3-oxo-heptanoicacid methyl ester (1.36 g, 3.8 mmol) from Step 3 above dissolved in MeOH(50 mL) was added a NaOH solution (2.8 M, 2.7 mL, 7.6 mmol). Thereaction was stirred at room temperature for 18 hours. The reaction wasthen quenched with acetic acid (0.44 mL, 7.7 mmol) and concentrated byrotary evaporation to an oil. The oil was dissolved in CH₂Cl₂ and washedwith water. The organic layer was separated, and dried over Na₂SO₄. Thesolids were removed by filtration, and the liquid was concentrated toyield the product (1.061 g, 86% yield).

MS (ESI): 324 (M−H).

Step 5: 6-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione

A solution of[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-carbamic acidtert-butyl ester (1.0 g, 2.8 mmol) from Step 4 above in 10% TFA/CH₂Cl₂was stirred at room temperature for 20 minutes. The reaction wasconcentrated by rotary evaporation and used as is without furtherpurification.

MS (ESI): 224 (M−H).

Example H(2) Furan-2-carboxylic acid[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-amide

The desired product was prepared analogously to Example H(1),substituting 2-furanoic acid (54 mg, 0.48 mmol) in place of3-furan-2-yl-propionic acid. Yield: 28 mg, 22%.

¹H NMR (CDCl₃) δ: 1.46-3.29 (m, 21H), 6.62 (s, 1H), 7.20 (s, 1H), 7.58(s, 1H). MS (ESI): 318 (M−H).

Example H(3) }N-[3-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-propyl]-3-furan-2-yl-propionamide

The desired product was prepared analogously to example H(1)substituting 6-(3-Amino-propyl)-6-cyclopentyl-dihydro-pyran-2,4-dione(62 mg, 0.26 mmol) in place of36-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield: 12 mg,13%.

¹H NMR (CDCl₃) δ: 1.10-1.47 (m, 8H), 2.09-2.39 (m, 8H), 2.55-2.66 (m,3H), 2.74-2.94 (m, 4H), 5.68 (s, 1H), 5.93 (s, 1H), 6.96 (s, 1H). MS(ESI): 360 (M−H).

Example H(4):N-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-3-furan-2-yl-propionamide

The desired product was prepared analogously to example F(7),substitutingN-[2-(5-chloro-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-3-furan-2-yl-propionamidefrom Step 3 below in place of3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dioneand 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol in place of2-mercaptothiazole. Yield: 11 mg, 8%. MS (ESI): 524 (M−H).

Step 1: 3-Amino-1-cyclopentyl-propan-1-one

The desired product was prepared analogously to example H(1), Step 5,substituting (3-Cyclopentyl-3-oxo-propyl)-carbamic acid tert-butyl ester(described in Step 2 of example H(1)) in place of[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-carbamic acidtert-butyl ester.

MS (ESI): 142 (M+H).

Step 2: N-(3-Cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide

The desired product was prepared analogously to example H(1),substituting 3-amino-1-cyclopentyl-propan-1-one (0.874 g, 6.2 mmol) fromStep 1 above in place of6-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield: 0.901 g,55%.

¹H NMR (CDCl₃) δ: 1.33-1.60 (m, 8H), 2.24 (t, J=7.58 Hz, 2H), 2.42-2.48(m, 3H), 2.73 (t, J=7.45 Hz, 2H), 3.24 (q, J=6.06 Hz, 2H), 5.78 (d,J=3.79 Hz, 1H), 6.03 (d, J=6.03 Hz, 1H), 7.06 (d, J=2.53 Hz, 1H).

Step 3:N-[2-(5-Chloro-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-3-furan-2-yl-propionamide

The desired product was prepared analogously to example F(1), Step 2,substituting N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide(300 mg, 1.1 mmol) from Step 2 above in place of1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one andmethyl 2-chloroacetoacetate (0.7 mL, 5.7 mmol) in place of methylacetoacetate. Yield: 103 mg, 14%.

MS (ESI): 380 (M−H), 382 (M+2−H).

Example H(5)3-Cyclopentyl-5-(3-furan-2-yl-propionylamino)-3-hydroxy-pentanoic Acid

A solution of NaOH (0.3 M, 1.6 mL, 0.49 mmol) was added to3-cyclopentyl-5-(3-furan-2-yl-propionylamino)-3-hydroxy-pentanoic acidethyl ester (86 mg, 0.245 mmol) from Step 1 below and stirred at roomtemperature until complete by HPLC. The reaction was diluted with 10 mLCH₂Cl₂, and washed with 10 mL saturated NH₄Cl. The aqueous layer wasextracted with 2×10 mL CH₂Cl₂, and the organic layers were combined.After concentrating by rotary evaporation, the residue was purified byflash chromatography to give the desired compound (29 mg, 37% yield).

¹H NMR (CDCl₃) δ: 1.39-1.75 (m, 8H), 2.00-2.09 (m, 2H), 2.39-2.52 (m,5H), 2.90 (t, J=7.45 Hz, 2H), 3.29-3.40 (m, 2H), 5.96 (s, 1H), 6.2 (s,1H), 6.31 (br, 1H), 7.23 (s, 1H). MS (ESI): 322 (M−H).

Step 1:3-Cyclopentyl-5-(3-furan-2-yl-propionylamino)-3-hydroxy-pentanoic AcidEthyl Ester

To a solution of LDA (1.0 M, 1.1 mL, 1.1 mmol) cooled to −78° C. wasadded EtOAc (0.1 mL, 1.1 mmol). After stirring for 30 minutes, asolution of N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide(100 mg, 0.38 mmol; described in Step 2 of example H(4)) dissolved in 3mL THF was added. The reaction was stirred for 2 hours and then allowedto warm to −40° C. The reaction was quenched with 10 mL saturated NH₄Cl,and the layers were separated. The aqueous layer was extracted with 3×10mL CH₂Cl₂, and the organic layers were combined. After concentrating theorganic layers by rotary evaporation, the product was purified by flashchromatography (86 mg, 64% yield). MS (ESI): 350 (M−H).

Example I(1)6-cyclopentyl-6-[(pyrimidin-2-ylthio)methyl]dihydro-2H-pyran-2,4(3H)-dion

The title compound was prepared analogously to Example A(6), wherepyrimidine-2-thiol was substituted in place of p-methoxythiophenol inStep 2 of that example.

¹H NMR (CDCl₃): δ 1.6-2.0 (brm, 8H), 2.48 (m, 1H), 2.66 (s, 1H), 2.86(s, 1H), 3.66 (s, 1H), 3.43 (s, 2H), 3.70-3.74 (m, 2H), 3.78 (d, J=7.54Hz, 1H), 7.03 (t, J=4.90 Hz, 1H), 8.50, (d, J=4.71 Hz, 2H). Anal. Calcd.For C₁₅H₁₈N₂O₃S: C, 58.80; H, 5.92; N, 9.14. Found: C, 58.95; H, 6.04;N, 9.20.

Example I(2)6-cyclopentyl-6-{[(2-furylmethyl)thio]methyl}dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(6), where2-furylmethanethiol was substituted in place of p-methoxythiophenol inStep 2 of that example.

¹H NMR (CDCl₃): δ 1.31-175 (brm, 8H), 2.25 (m, 1H), 2.68 (m, 2H),2.86-2.88 (m, 2H), 3.72 (s, 1H), 3.75 (s, 1H), 6.22 (d, J=1.88 Hz, 1H),6.32 (t, J=1.88 Hz, 1H), 7.38, (s, 1H). Anal. Calcd. For C₁₆H₂₀O₄S: C,62.31; H, 6.54. Found: C, 62.54; H, 6.37.

Example I(3)6-cyclopentyl-6-{[(6-ethoxy-1,3-benzothiazol-2-yl)thio]methyl}dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(6), where6-ethoxy-1,3-benzothiazole-2-thiol was substituted in place ofp-methoxythiophenol in Step 2 of that example. LCMS: 404, M-ve on APCI.Rf: 0.3; 98:2, DCM: MeOH, developed with anisaldehyde. Anal. Calcd. ForC₂₀H₂₃S₂O₄N: C, 59.24; H, 5.72; N, 3.45. Found: C, 56.50; H, 6.04; N,3.63.

Example I(4) 6-cyclopentyl-6{[(4-isopropylphenyl)thio]methyl}dihydro-2H-pyran-2,4(3H)-dione

The title compound was prepared analogously to Example A(6), where4-isopropylbenzenethiol was substituted in place of p-methoxythiophenolin Step 2 of that example.

¹H NMR (CDCl₃): δ 1.00 (m, 1H), 1.23 (d, J=6.97 Hz), 6H), 1.44-1.70(brm, 8H), 1.94 (m, 1H), 2.67 (m, 2H), 2.77 (s, 2H), 3.42 (s, 2H), 7.07,(d, J=8.10 Hz, 2H), 7.15 (d, J=8.10 Hz, 2H). Anal. Calcd. For C₂₀H₂₆O₃S:C, 69.33; H, 7.56. Found: C, 69.55; H, 7.70.

General Scheme for Resolution of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onePrecursors

Enantiomers A and B of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(Absolute Stereochemistry Not Known)

Step 1:1-cyclopentyl-1-[(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl]prop-2-ynylEthyl Oxalate

To a solution of racemic6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one(10 g, 37.9 mmol) in CH₂Cl₂(200 ml) was added triethylamine (3.0 eqv,113.7 mmol) at 0° C. Then ethyl chlorooxoacetate (3.0 eqv, 113.7 mmol)in CH₂Cl₂ (10 ml) was added dropwise over a 30-minute period underargon. The solution was allowed to stir overnight at room temperature.After removal of solvent, the crude product was purified using a flashcolumn (heptane: EtOAc, 3:1) to afford the desired oxalate (13.5g, >95%). API-MS: [M+Na⁺]: 387;

¹H NMR (CDCl₃, 300 MHz) δ: 5.27 (s, 1H), 4.33 (dq, J=2.5 and 7.5 Hz,2H), 2.67 (s, 2H), 2.64 (m, 1H), 1.65 (s, 6H), 1.40-1.80 (m, 6H), 1.36(dt, J=3.0 and 7.2 Hz, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ: 171.47, 165.83,163.62, 161.84, 107.31, 97.74, 83.33, 79.21, 77.58, 63.48, 46.65, 42.82,28.62, 28.62, 28.44, 25.28, 14.54, 14.44, 12.89.

Step 2: Enantiomer B of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one

To a 250 ml three-necked flask equipped with a pH electrode was added 72ml of phosphate buffer (pH 4.0, 0.5M) and Candida rugosa lipase (5 g,Amano AY). The mixture was stirred vigorously and then the oxalate (6 g)in 18 ml of acetonitrile was added. The reaction mixture was allowed tostir at 23° C. and the pH was kept at 4.0 using a pH titrator. Thereaction was monitored with HPLC and stopped after 50% conversion (<20hrs). The mixture was extracted by MTBE (×3) and the combined organiclayer was dried over MgSO4. After removal of the solvent, the crudeproduct was separated carefully by silica-gel chromatography, usingheptane/EtOAC (5:1, 2:1), which afforded 2.6 g of the oxalate (43%yield, 96% ee) and 2.0 g of product (enantiomer B: 46% yield, 92% ee).

¹H NMR (300 MHz, CDCl₃) δ: 1.45-1.80 (m, 8H), 1,72 (s, 3H), 1.74 (s,3H), 2.13-2.18 (m, 1H), 2.49 (s, 1H), 2.56 (s, 1H), 2.58 (s, 2H), 5.43(s, 1H).

Step 3: Enantiomer A of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one

To the optically pure oxalate (2.5 g, 15.1 mmol) in 50 ml of MeOH wasadded K₂CO₃ (2.0 g). The mixture was stirred at 23° C. for 8 h. Aftercomplete conversion, the mixture was neutralized with 1N HCl at coldtemperature. The aqueous solution was extracted with MTBE (×3) and theorganic layer was washed with brine and dry over MgSO₄. After removal ofMTBE, 1.75 g of the desired product (enantiomer A) was produced with95.5% ee and 96% yield.

¹H NMR (300 MHz, CDCl₃) δ: 1.45-1.80 (m, 8H), 1,72 (s, 3H), 1.74 (s,3H), 2.13-2.18 (m, 1H), 2.49 (s, 1H), 2.56 (s, 1H), 2.58 (s, 2H), 5.43(s, 1H).

Example J(1)6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Enantiomer A)

The title compound was prepared analogously to Example A(64), , whereEnantiomer A (described above) of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas substituted in place of the racemic material.

¹H NMR (300 MHz, CDCl₃)δ: ?1.34 (d, J=6.03 Hz, 6H), 1.61-1.77 (m, 8H),1.89-1.97 (m, 2H), 2.24-2.29 (m, 1H), 2.61 (t, J=8.38 Hz, 2H), 2.76 (s,2H), 3.43 (s, 2H), 4.44-4.52 (m, 1H), 6.79-6.92 (m, 3H).

HRMS calcd for C₂₁H₂₈O₄F (M+H⁺): 363.1966. Found: 363.1980.

Example J(2)6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione(Enantiomer B)

The title compound was prepared analogously to Example A(64), whereEnantiomer B (described above) of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas substituted in place of the racemic material.

¹H NMR (300 MHz, CDCl₃) δ: 1.34 (d, J=6.03 Hz, 6H), 1.61-1.77 (m, 8H),1.89-1.97 (m, 2H), 2.24-2.29 (m, 1H), 2.61 (t, J=8.38 Hz, 2H), 2.76 (s,2H), 3.43 (s, 2H), 4.44-4.52 (m, 1H), 6.79-6.92 (m, 3H). ESI-MS calcdfor C₂₁H₂₇O₄F: 362.2. Found (M+Na⁺): 385.1.

Example J(3)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one(Enantiomer A)

The title compound was prepared analogously to Example B(31), whereEnantiomer A of6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.

¹H NMR (300 MHz, CDCl₃)δ: ?1.32 (d, J=6.03 Hz, 6H), 1.50-1.80 (m, 8H),1.95-2.01 (m, 2H), 2.33-2.41 (m, 1H), 2.56-2.62 (m, 3H), 2.66 (s, 3H),2.71-2.73 (m, 1H), 2.79 (s, 3H), 4.09 (s, 2H), 4.414.50 (m, 1H),6.78-6.88 (m, 4H). HRMS calcd for C₂₉H₃₆N₄O₄F (M+H⁺): 523.2715. Found:523.2708.

Example J(4)6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one(Enantiomer B)

The title compound was prepared analogously to Example B(31), whereEnantiomer B of6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dionewas substituted in place of6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione.

¹H NMR (300 MHz, CDCl₃)δ: ?1.32 (d, J=6.03 Hz, 6H), 1.50-1.80 (m, 8H),1.95-2.01 (m, 2H), 2.33-2.41 (m, 1H), 2.56-2.62 (m, 3H), 2.66 (s, 3H),2.71-2.73 (m, 1H), 2.79 (s, 3H), 4.09 (s, 2H), 4.41-4.50 (m, 1 H),6.78-6.88 (m, 4H). HRMS calcd for C₂₉H₃₆N₄O₄F (M+H⁺): 523.2715. Found:523.2699.

Example J(5)6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Enantiomer A)

The title compound was prepared analogously to Example A(64), where1-Bromo-3-ethyl-benzene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene in that example, and Enantiomer A of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas used in place of the racemic alkyne.

¹H NMR (CDCl₃): δ 1.23 (t, 3H, J=7.6 Hz), 1.50-1.83 (br m, 8H),1.91-2.05 (m, 2H), 2.29 (m, 1H), 2.59-2.68 (m, 4H) 2.27, (s, 2H), 3.42(s, 2H), 6.96 (m, 2H), 7.06 (d, 1H, J=7.01 Hz), 7.21 (t, 1H, J=8.0 Hz).ESIMS: MH⁺315.20, MH⁻313.20.

Example J(6)6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Enantiomer B)

The title compound was prepared analogously to Example A(64), where1-Bromo-3-ethyl-benzene was substituted in place of4-bromo-2-fluoro-1-isopropylbenzene of that example and Enantiomer B of6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-onewas used in place of the racemic alkyne.

¹H NMR (CDCl₃): δ 1.23 (t, 3H, J=7.6 Hz), 1.50-1.83 (br m, 8H),1.91-2.05 (m, 2H), 2.29 (m, 1H), 2.59-2.68 (m, 4H) 2.27, (s, 2H), 3.42(s, 2H), 6.96 (m, 2H), 7.06 (d, 1H, J=7.01 Hz), 7.21 (t, 1H, J=8.0 Hz).ESIMS: MH⁺315.20, MH⁻313.20.

Example J(7)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(Enantiomer A)

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Enantiomer A) (Example J(6)) to5,7-Dimethyl-[1,2,4]triazolo[1,5-?]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

¹H NMR (DMSO-d₆): δ 1.18 (t, 3H, J=7.6 Hz), 1.46-1.76 (br m, 8H), 2.18(m, 2H), 2.48-2.67 (m, 12H), 2.85 (d, 1H, J=17.4 Hz), 3.78 (d, 1H,J=16.3 Hz), 3.91 (d, 1H, J=16.3 Hz), 7.08 (m, 4H), 7.22 (t, 1H, J=7.6Hz), 10.91 (s, 1H). C₂₈H₃₄N₄O₃ (M+H)⁺475.20.

Example J(8)6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one(Enantiomer B)

¹H NMR (DMSO-d₆): δ 1.18 (t, 3H, J=7.6 Hz), 1.46-1.76 (br m, 8H), 2.18(m, 2H), 2.48-2.67 (m, 12H), 2.85 (d, 1H, J=17.4 Hz), 3.78 (d, 1H,J=16.3 Hz), 3.91 (d, 1H, J=16.3 Hz), 7.08 (m, 4H), 7.22 (t, 1H, J=7.6Hz), 10.91 (s, 1H). C₂₈H₃₄N₄O₃ (M+H)⁺475.20.

The title compound was prepared by coupling6-Cyclopentyl-6-[2-(3-ethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione(Enantiomer B) (Example J(7)) to5,7-Dimethyl-[1,2,4]triazolo[1,5-?]pyrimidine-2-carbaldehyde using theMe₂NHBH₃ method described in the synthesis of Example B(31).

The compounds of the present invention are potent inhibitors ofHepatitis C virus, in particular HCV replication, and even in moreparticular, HCV RNA-dependent RNA-polymerase.

The compounds are all adapted to therapeutic use as anti-HCV agents inmammals, particularly in humans.

The active compound may be applied as a sole therapy or may involve oneor more other antiviral substances, for example those selected from, forexample, HCV inhibitors such as interferon alphacon-1, naturalinterferon, interferon beta-1a, interferon omega, interferon gamma-1b,interleukin-10, BILN 2061 (serine protease), amantadine (Symmetrel),thymozine alpha-1, viramidine; HIV inhibitors such as nelfinavir,delavirdine, indinavir, nevirapine, ritonavir, saquinavir, andtenofovir. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof the treatment. The in vitro activity of the compounds of formula 1may be determined by the following procedure.

The compounds described herein were tested for activity with HCVpolymerase. Recombinant HCV polymerase was tested for its ability toperform primer/template-directed transcription in assays that contained30 mM tris-HCl pH 7.2, 10 mM MgCl₂, 20 mM NaCl, 1 mM Dithiothreitol(DTT), 0.05% Tween-20, 1% glycerol, 5 pmoles biotin-dG₁₂ (primer), 0.5pmoles poly(rC)₃₀₀ (template), 1 μM GTP, 0.1-0.3 uCi α-³²P-GTP, and 2.5pmoles (0.15 μg) HCV polymerase protein in a final volume of 75 μL.Reactions were initiated by addition of enzyme and incubated 30 minutesat 30° C. Reactions were stopped by addition of 33 mM EDTA, andpolynucleotide products were collected by filtration throughDiethylaminoethyl (DE) Filtermat papers (Wallac). Unincorporatedtriphosphate was removed by washing the filters with 5% dibasic sodiumphosphate. The filters were counted in a Packard Tri-Lux Microbetascintillation counter (Packard Bioscience, Meriden, Conn.). Compounds tobe tested were added at various concentrations, e.g., 1 μm to 50 μm,from stocks in 10% DMSO-water (final DMSO is 1% in reaction).

IC₅₀ values were estimated from the primary cpm data (collected intriplicate) using the formula: cpm (I)=cpm (noinhibitor)(1-([I]/([I]+IC₅₀))). An IC₅₀ value represents theconcentration (in μM) of a compound that provides 50% inhibition ofpolymerase-directed transcription in the above assay. A percentinhibition value is expressed for a compound where it was impractical tocalculate an IC₅₀ value with available data. If the IC₅₀ estimated bythe above equation was less than 200 nM, it was recalculated using thefollowing equation, which takes into account the enzyme concentration(30 nM) in the assay: cpm(I)=cpm(noinhibitor)(1-((((I+IC₅₀+30e−9)-sqrt(((I+IC₅₀+30e−9)²)-4×30e−9×I)))/((2)(30e-9))). Curve fitting was performed using the program KaleidaGraph(Synergy Software, Reading, Pa.).

Inhibition concentration (IC₅₀) data as determined for exemplarycompounds of the invention are presented in Table 1 below. TABLE 1Example ( ) IC50 (μM) Example A(01) 38.3 Example A(02) 2.4 Example A(03)4.3 Example A(04) 5.6 Example A(05) 5.1 Example A(06) 23.5 Example A(07)13.4 Example A(08) 6 Example A(09) 5.5 Example A(10) 8.1 Example A(11)16.7 Example A(12) 18.3 Example A(13) 63 Example A(14) 35% @ 50 uMExample A(15) 4.4 Example A(16) 14.4 Example A(17) 23 Example A(18) 3.1Example A(19) 37% @ 50 uM Example A(20) 32 Example A(21) 12.3 ExampleA(22) 0.3 Example A(23) 1% @ 50 uM Example A(24) 29% @ 50 uM ExampleA(25) 73.9 Example A(26) 20% @ 50 uM Example A(27) 0.125 Example A(28)3.9 Example A(29) 1.5 Example A(30) 0.84 Example A(31) 0.4 Example A(32)5.2 Example A(33) 5 Example A(34) 10 Example A(35) 4.1 Example A(36) 8.4Example A(37) 8.7 Example A(38) 12 Example A(39) 14% @ 50 uM ExampleA(40) 2 Example A(41) 13 Example A(42) 8 Example A(43) 20 Example A(44)68.3 Example A(45) 30 Example A(46) 73 Example A(47) 7 Example A(48)33.2 Example A(49) 9 Example A(50) 5.9 Example A(51) 3.9 Example A(52)1.5 Example A(53) 3.3 Example A(54) 2.9 Example A(55) 11.2 Example A(56)39 Example A(57) 6.3 Example A(58) 6.5 Example A(59) 3.2 Example A(60)8.7 Example A(61) 40% @ 50 uM Example A(62) 8.3 Example A(63) 11 ExampleA(64) 4 Example A(65) 1.3 Example A(66) 3.6 Example A(67) 24% @ 20 uMExample A(68) 3.4 Example A(69) 9.9 Example A(70) 9.4 Example A(71) 1.9Example A(72) 1.5 Example A(73) 3.3 Example A(74) 1.2 Example A(75) 7.1Example A(76) 5.8 Example A(77) 24 Example A(78) 21 Example A(79) 1Example A(80) 20 Example A(81) 0.14 Example A(82) 11% @ 20 uM ExampleA(83) 5.4 Example A(84) 6.8 Example A(85) 12.4 Example A(86) 0.4 ExampleA(87) 0.89 Example A(88) 2.3 Example A(89) 2.8 Example A(90) 0.77Example A(91) 0.5 Example A(92) 1 Example A(93) 0.7 Example A(94) 4Example A(95) 2.1 Example A(96) 3.2 Example A(97) 0.29 Example A(98)0.01 Example A(99) 0.017 Example A(100) 0.088 Example A(101) 0.066Example A(102) 0.005 Example A(103) 0.18 Example A(104) 0.008 ExampleA(105) NA Example A(106) NA Example A(107) 0.36 Example A(108) 0.003Example A(109) 0.004 Example A(110) 0.001 Example A(111) 0.002 ExampleA(112) 0.006 Example A(113) 0.008 Example A(114) 0.01 Example A(115)0.005 Example A(116) NA Example A(117) NA Example A(118) 3.2 ExampleA(119) 1.2 Example A(120) 13 Example A(121) 1.3 Example A(122) 31Example A(123) 0.012 Example A(124) 0.35 Example A(125) 0.011 ExampleA(126) 0.009 Example A(127) 0.005 Example A(128) 0.49 Example A(129) 8.9Example A(130) 1.3 Example A(131) 0.137 Example A(132) 13 Example A(133)0.072 Example A(134) 38 Example A(135) 0.015 Example A(136) 0.002Example A(137) 0.007 Example A(138) 0.008 Example A(139) 0.002 ExampleA(140) NA Example A(141) NA Example A(142) 0.004 Example A(143) 0.009Example A(144) 0.011 Example A(145) 3.9 Example A(146) 0.002 ExampleA(147) 1.4 Example A(148) 0.005 Example A(149) 3.9 Example A(150) 0.007Example A(151) 0.3 Example A(152) 0.001 Example A(153) 0.003 ExampleA(154) 0.005 Example A(155) 0.003 Example A(156) 0.021 Example A(157)0.065 Example A(158) NA Example A(159) NA Example A(160) 0.029 ExampleA(161) 0.008 Example A(162) 0.01 Example A(163) 1.9 Example A(164) 0.042Example A(165) NA Example A(166) 0.001 Example A(167) 0.004 ExampleA(168) 0.009 Example A(169) 0.4 Example A(170) 0.01 Example A(171) 0.004Example A(172) 0.006 Example A(173) 0.004 Example A(174) 0.006 ExampleA(175) 0.009 Example A(176) 0.006 Example A(177) 0.014 Example A(178)1.3 Example A(179) 0.005 Example A(180) 0.01 Example A(181) 0.6 ExampleA(182) 0.004 Example A(183) 0.007 Example A(184) 0.52 Example A(185)0.008 Example A(186) 0.04 Example A(187) 0.004 Example A(188) 0.006Example A(189) 2.9 Example A(190) 0.011 Example A(191) 0.017 ExampleA(192) 0.028 Example A(193) 0.098 Example A(194) 6.9 Example A(195) 11Example A(196) 0.007 Example A(197) 0.006 Example A(198) 0.016 ExampleA(199) 0.01 Example A(200) 0.005 Example A(201) 0.012 Example A(202)0.012 Example A(203) 0.02 Example A(204) 0.017 Example A(205) 0.001Example A(206) Example A(207) 0.004 Example A(208) 0.007 Example A(209)0.05 Example A(210) 0.002 Example A(211) 0.004 Example A(212) 0.004Example A(213) 0.0045 Example A(214) 0.038 Example A(215) 4.9 ExampleA(216) 0.045 Example A(217) 0.014 Example A(218) 0.061 Example A(219)0.088 Example A(220) 0.172 Example A(221) 0.014 Example A(222) 0.12Example A(223) 0.005 Example A(224) 0.004 Example A(225) 0.003 ExampleA(226) 0.0.039 Example A(227) 0.01 Example A(228) 0.47 Example A(229)0.01 Example A(230) 0.011 Example A(231) 0.006 Example A(232) 0.004Example A(233) 0.011 Example A(234) 0.011 Example A(235) 0.89 ExampleA(236) 0.003 Example A(237) 1.0 Example A(238) 0.01 Example A(239) 0.003Example A(240) 0.009 Example A(241) 0.8 Example A(242) NA Example A(243)NA Example A(244) NA Example A(245) NA Example A(246) NA Example A(247)NA Example A(248) 0.016 Example A(249) 0.019 Example A(250) NA ExampleA(251) NA Example A(252) 0.01 Example A(253) 0.006 Example A(254) 0.012Example A(255) 1.9 Example A(256) NA Example A(257) 0.04 Example A(258)0.002 Example A(259) 0.006 Example A(260) 0.007 Example A(261) 0.004Example A(262) 0.006 Example A(263) 0.007 Example A(264) 0.004 ExampleA(265) 0.004 Example A(266) 0.019 Example A(267) 0.004 Example A(268)0.6

Example A(269) 0.026 Example A(270) 0.037 Example A(271) 0.006 ExampleA(272) 0.006 Example B(01) 0.015 Example B(02) 0.027 Example B(03) 0.005Example B(04 0.024 Example B(05) 0.13 Example B(06) 0.15 Example B(07)0.001 Example B(08) 0.013 Example B(09) 0.054 Example B(10) 0.053Example B(11) 0.019 Example B(12) 0.026 Example B(13) 0.02 Example B(14)0.63 Example B(16) 0.9 Example B(17) 1.1 Example B(18) 0.021 ExampleB(19) 0.06 Example B(20) 0.004 Example B(21) 0.4 Example B(22) 1.2Example B(23) 0.87 Example B(24) 0.14 Example B(25) 0.24 Example B(26)2.3 Example B(27) 47% @ 20 uM Example B(28) 0.011 Example B(29) 0.22Example B(30) 2 Example B(31) 0.003 Example B(32) 0.07 Example B(33)0.136 Example B(34) 0.03 Example B(35) 0.07 Example B(36) 0.042 ExampleB(37) 0.008 Example B(38) 0.021 Example B(39) 0.029 Example B(40) 0.014Example B(41) 0.12 Example B(42) 0.21 Example B(43) 0.36 Example B(44)0.053 Example B(45) 0.053 Example B(46) 0.02 Example B(47) 0.8 ExampleB(48) 0.7 Example B(49) 0.01 Example B(50) 0.09 Example B(51) 0.072Example B(52) 0.17 Example B(53) 0.35 Example B(54) 0.3 Example B(55)0.15 Example B(56) 0.1 Example B(57) 0.05 Example B(58) 6.2 ExampleB(59) 0.006 Example B(60) 0.54 Example B(61) 0.12 Example B(62) 0.2Example B(63) 0.016 Example B(64) 0.033 Example B(65) 0.11 Example B(66)0.22 Example B(67) 3.2 Example B(68) 0.1 Example B(69) 0.8 Example B(70)0.24 Example B(71) 0.08 Example B(72) 1.4 Example B(73) 0.062 ExampleB(74) 3.4 Example B(75) 0.003 Example B(76) 0.001 Example B(77) 5.5Example B(78) 1 Example B(79) 2.4 Example B(80) 0.56 Example B(81) ˜0.24uM Example B(82) 0.68 Example B(83) 0.36 Example B(84) 0.11 ExampleB(85) 0.74 Example B(86) 22.1 Example B(87) 1.8 Example B(88) 5.1Example B(89) 0.185 Example B(90) 0.006 Example B(91) 0.01 Example B(92)0.008 Example B(93) 0.09 Example B(94) 1% Example B(95) 0.013 ExampleB(96) 0.005 Example B(97) 0.009 Example B(98) 0.006 Example B(99) 0.35Example B(100) 0.003 Example B(101) 0.61 Example B(102) 0.5 ExampleB(103) 0.107 Example B(104) 0.003 Example B(105) 0.046 Example B(106) NAExample B(107) 0.006 Example B(108) NA Example B(109) 23% @ 50 uMExample B(110) 0.107 Example B(111) 0.321 Example B(112) 0.097 ExampleB(113) 0.019 Example B(114) 0.016 Example B(115) 3.3 Example B(116)0.011 Example B(117) 0.111 Example B(118) 0.2 Example B(119) 0.07Example B(120) 0.012 Example B(121) 6 Example B(122) 0.007 ExampleB(123) 0.58 Example B(124) 0.09 Example B(125) 0.004 Example B(126)0.023 Example C(01) 0.337 Example C(02) 0.014 Example C(03) 0.5 ExampleC(04) 1.8 Example C(06) 0.25 Example C(07) 0.019 Example C(08) 0.31Example C(09) 0.326 Example C(10) 0.016 Example C(11) 0.19 Example C(12)0.082 Example C(13) 0.016 Example C(14) 0.014 Example C(15) 22% @ 20 uMExample C(16) 8% @ 20 uM Example C(17) 2% @ 50 uM Example C(18) 2% @ 50uM Example C(19) 22% @ 50 uM Example C(20) 11% @ 50 uM Example C(21) 12%@ 50 uM Example C(22) 0.068 Example C(23) 0.05 Example C(24) 0.051Example C(25) 0.02 Example C(26) 0.13 Example C(27) 2.5 Example C(28) 8Example C(29) 9.3 Example C(30) 0.55 Example C(31) 0.51 Example C(32)0.27 Example C(33) 0.26 Example C(34) 0.053 Example C(35) 0.07 ExampleC(36) 0.079 Example C(37) 0.13 Example C(38) 0.28 Example C(39) 0.22Example C(40) 0.025 Example C(41) 0.17 Example C(42) 0.013 Example C(43)0.035 Example C(44) 0.18 Example C(45) 3.2 Example C(46) 0.037 ExampleC(47) 0.24 Example C(48) 0.14 Example C(49) 0.08 Example C(50) 0.01Example C(51) 0.256 Example C(52) 0.14 Example C(53) 0.067 Example C(54)0.22 Example C(55) 0.03 Example C(56) 1.3 Example C(57) 0.002 ExampleC(58) 0.14 Example C(59) 0.2 Example C(60) 0.015 Example C(61) 0.14Example C(62) 0.5 Example C(63) 0.008 Example C(64) 0.012 Example C(65)0.054 Example C(66) 0.9 Example C(67) 0.05 Example C(68) 0.2 ExampleC(69) 0.13 Example C(70) 0.0074 Example C(71) 0.058 Example C(72) 0.078Example C(73) 0.035 Example C(74) 0.099 Example C(75) 0.044 ExampleC(76) 0.053 Example C(77) 0.062 Example C(78) 0.047 Example C(79) 0.063Example C(80) 0.031 Example C(81) 0.014 Example C(82) 0.027 ExampleC(83) 0.04 Example C(84) 0.033 Example C(85) 0.035 Example C(86) 0.048Example C(87) 0.028 Example C(88) 0.022 Example C(89) 0.02 Example C(90)0.04 Example C(91) 0.04 Example C(92) 0.082 Example C(93) 0.014 ExampleC(94) 0.087 Example C(95) 0.074 Example C(96) 0.075 Example C(97) 0.12Example C(98) 0.068 Example C(99) 0.079 Example C(100) 0.032 ExampleC(101) 0.14 Example C(102) 0.038 Example C(103) 0.24 Example C(104) 0.31Example C(105) 0.2 Example C(106) 0.24 Example C(107) 0.16 ExampleC(108) 0.21 Example C(109) 0.9 Example C(110) 7.6 Example C(111) 0.395Example C(112) 0.064 Example D(01) 0.41 Example D(02) 0.54 Example D(03)1.5 Example D(04) 0.054 Example D(05) 6.8 Example D(06) 1.3 ExampleD(07) 0.32 Example D(08) 2.3 Example E(1) 22 Example E(2) 8.2 ExampleE(3) 65 Example F(1) 7.2 Example F(2) 7.2 Example F(3) 8.4 Example F(4)5.8 Example F(5) 25 Example F(6) 83 Example F(7) 7.5 Example G(1) 16% @20 uM Example G(2) 3% @ 20 uM Example G(3) 29 Example H(1) 1 ExampleH(2) 51 Example H(3) 1.2 Example H(4) 60 Example H(5) 7% @ 50 uM ExampleI(1) 27% @ 50 uM Example I(2) 22% @ 50 uM Example I(3) −2% @ 50 uMExample I(4) 44% @ 50 uM Example J(1) 4.4 Example J(2) 3.9 Example J(3)0.005 Example J(4) 0.019 Example J(5) 1.9 Example J(6) 1.2 Example J(7)0.01 Example J(8) 0.014

The examples and preparations provided above further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations.

1-4. (canceled)
 5. Compounds of formula (4),

wherein: R¹ is cyclopentyl; R³ is —(CR⁸R⁹)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, and the heterocyclicmoiety is optionally substituted by 1 to 5 R⁴ groups; each R⁴ isindependently chosen from halo. C₁-C₁₀ alkyl, and R⁶—O—, and each C₁-C₁₀alkyl may be optionally substituted by at least one substituent chosenfrom halo, trifluoromethyl, trifluoromethoxy, C₁-C₁₀ alkyl, and cyano;or when two adjacent R⁴ groups are both C₁-C₁₀ alkyl, they, togetherwith the atoms to which they are attached, form a 3- to 7-membered ring,wherein in said ring any carbon atom may be replaced by a heteroatomchosen from N, O, and S, provided that two adjacent carbons are not bothreplaced by heteroatoms; R⁶ is hydrogen or C₁-C₁₀ alkyl; R⁸ and R⁹ arehydrogen; z is an integer from 1 to 5; and y is an integer from 0 to 5.6. Compounds according to claim 5, wherein: R³ is—(CH₂)_(t)([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally substituted by1 to 3 R⁴ groups; t is an integer from 1-3; and y is an integer from 1to
 3. 7. Compounds according to claim 6, wherein: R³ is—(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by 1 to 3 R⁴groups; each R⁴ is independently chosen from halo and C₁-C₁₀ alkyloptionally substituted with cyano; or two adjacent R⁴ groups are bothC₁-C₁₀ alkyl and, together with the atoms to which they are attached,form a 3- to 7-membered ring, wherein a carbon atom is replaced by aheteroatom chosen from N, O, and S; z is an integer from 2 to 3; and yis
 2. 8. Compounds according to claim 7, wherein: R³ is—(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by 2 R⁴ groups;and each R⁴ is independently chosen from halo, —CH₃, and —C(CH₃)₂CN. 9.Compounds according to claim 7, wherein two adjacent R⁴ groups are bothC₁-C₁₀ alkyl and, together with the atoms to which they are attached,form a 3- to 7-membered ring, wherein a carbon atom is replaced by aheteroatom chosen from N, O, and S.
 10. Compounds according to claim 9,wherein: R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted byat least one substituent chosen from halo and methyl; and two adjacentR⁴ groups, together with the atoms to which they are attached form a5-membered ring, wherein in said ring one carbon atom is replaced by O.11. Compounds of formula (4b),

wherein: R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted byat least one substituent chosen from halo and methyl; Q is chosen fromN, O, and S; R^(4a), R^(4b), and R^(4c) are independently chosen fromhydrogen, halo, C₁-C₁₀ alkyl, and R⁶—O—; and R⁶ is chosen from hydrogenand C₁-C₁₀ alkyl.
 12. Compounds of formula (5),

wherein: R^(4a), R^(4b), and R^(4c) are independently chosen from haloand C₁-C₁₀ alkyl; R^(4d), R^(4e), and R^(4f) are independently chosenfrom halo, R⁶—O—, and C₁-C₁₀ alkyl, wherein said C₁-C₁₀ alkyl isoptionally substituted with at least one substituent chosen from haloand cyano; and R⁶ is C₁-C₁₀ alkyl or hydrogen.
 13. Compounds of formula(6),

wherein R⁴ is halo.
 14. Compounds according to claim 13, wherein R⁴ ischosen from fluorine and chlorine.
 15. Compounds of formula (7),

wherein R⁴ is halo.
 16. Compounds according to claim 15, wherein R⁴ ischosen from fluorine and chlorine.
 17. Compounds of formula (8),

wherein R⁴ is halo.
 18. Compounds according to claim 17, wherein R⁴ ischosen from fluorine and chlorine.
 19. Compounds according to claim 6,wherein: R³ is —(CH₂)([1,2,4]triazolo[1,5-a]pyrimidinyl), optionallysubstituted by 1 to 3 R⁴ groups; each R⁴ is independently chosen fromhalo, C₁-C₁₀ alkyl, and R⁶—O—, and each C₁-C₁₀ alkyl may be optionallysubstituted by at least one substituent chosen from halo,trifluoromethyl, trifluoromethoxy, C₁-C₁₀ alkyl, and cyano; z is aninteger from 1 to 3; and y is
 2. 20. Compounds according to claim 19,wherein: R⁶ is hydrogen or methyl; and z is an integer from 2-3. 21.Compounds of formula (9),

wherein: R^(4a) is halo or C₁-C₁₀ alkyl; R^(4b), R^(4c), and R^(4d) areindependently chosen from C₁-C₁₀ alkyl and R⁶—O—; and R⁶ is hydrogen ormethyl.
 22. Compounds according to claim 21, wherein: R^(4a) is halo;R^(4b) and R^(4c) are each R⁶—O—; and R^(4d) is C₁-C₁₀ alkyl. 23.Compounds according to claim 22, wherein: R^(4a) is fluorine orchlorine; R^(4b) is —OCH₃; R^(4c) is —OH; and R^(4d) is —CH₂CH₃. 24.Compounds according to claim 23, wherein R^(4a) is chlorine.
 25. Acompound of formula (10),


26. A compound of formula (11),


27. A compound chosen from:6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a-pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione;7-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one;6N-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]4,6-dioxotetrahydro-2H-pyran-2-yl}ethyl)-2-ethylphenyl]-N-methylmethanesulfonamide;2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(1-methyl-1H-indol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;3-(5-Chloro-1-isopropyl-1-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;5-{6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}4-methyl-4H-[1,2,4]triazole-3-carboxylicacid methyl ester;3-(5-Chloro-1-methyl-1H-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-{[5-(2-furyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one;6-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;8-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-1,7-dihydro-6H-purin-6-one;6-[2-(5-chlor-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[5-(4-hydroxyphenyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one;ethyl2-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate;6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile;2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;(+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;(−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile;1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one;3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-hydroxy-3-propylphenyl)ethyl]-5,6-dihydro-2H-pyran-2-one;6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile;2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(+)-2-(4-[2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;(−)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;(+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;and pharmaceutically acceptable salts, solvates and prodrugs of theforegoing compounds.
 28. A compound chosen from:2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo1,5-a]pyrimidin-2-ylmethyl)4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;(+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;(−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;(+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(+)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;(−)-2-(4-(2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;(+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;and pharmaceutically acceptable salts, solvates and prodrugs of theforegoing compounds.
 29. A compound chosen from:(+)-2-(4-[2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;(−)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl-2-methylpropionitrile;(+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;(+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;and pharmaceutically acceptable salts, solvates and prodrugs of theforegoing compounds.
 30. A method of treating Hepatitis C virus in amammal, comprising administering to said mammal an amount of a compoundaccording to claim 5 that is effective in treating HCV.
 31. A method ofinhibiting Hepatitis C virus polymerase, comprising contacting saidpolymerase with a polymerase-inhibiting amount of a compound accordingto claim
 5. 32. A pharmaceutical composition for the treatment ofHepatitis C virus in a mammal, comprising an amount of a compoundaccording to claim 5 that is effective in treating Hepatitis C virus,and a pharmaceutically acceptable carrier.